MDM2 inhibitors

Abstract

The present invention relates to peptide therapeutics, and in particular to inhibitors of MDM2:MDM2 homodimerisation and MDM2:MDMX heterodimerisation, which may find use inter alia in the treatment of hyperproliferative disorders. The inhibitors find use in various medical applications, including the treatment of cancer.

Description

[0001] MDM2 inhibitors

[0002] This application claims priority from GB 2413802.6, filed 19 September 2024, the contents and elements of which are herein incorporated by reference for all purposes.

[0003] Field of the Invention

[0004] The present invention relates to peptide therapeutics, and in particular to inhibitors of MDM2:MDM2 homodimerisation and MDM2:MDMX heterodimerisation, which may find use inter alia in the treatment of hyperproliferative disorders.

[0005] Background

[0006] The mouse double minute 2 homolog (MDM2) is encoded in humans by the mdm2 gene. The full length transcript encodes a protein of 491 amino acids containing an N-terminal p53 interaction domain, a central acidic domain containing phosphorylation sites and nuclear import and export signals, a zinc finger domain, and a C-terminal RING domain which contains two coordinated zinc ions and possesses E3 ubiquitin ligase activity.

[0007] MDM2 is active either as a homodimer (MDM2:MDM2) or as a heterodimer with MDMX, also designated MDM4 (MDM2:MDMX). Dimerisation is mediated via the RING domain, and is necessary for E3 ubiquitin ligase activity.

[0008] Amplification or overexpression of MDM2, alone or in combination with MDMX, is frequently observed as a major driver of cancer, often associated with poor patient prognosis and treatment resistance (1). Current clinical therapeutics which target MDM2 or MDMX rely on their ability to bind p53, a major tumour suppressor protein encoded by the TP53 gene (2). In doing so, these therapies suppress the ability of MDM2 homo- or heterodimers to negatively regulate p53, preventing their inhibition of p53 anti-tumour transcriptional activity and p53 protein degradation via the ubiquitin proteosome system (UPS).

[0009] Reducing the influence of MDM2’s E3 ligase over p53 results in increased p53 tumour suppressor activity and promotes cancer cell death in the context of TP53 wild-type cancers. Therapeutics capable of exploiting the MDM2 / MDMX / p53 signaling axis have shown clear therapeutic utility, as seen by the track record of targeted therapeutics progressing into mid to late-stage clinical trials (e.g., Idasanutlin and ALRN-6924) (2). Nevertheless, such MDM2-targeted therapies typically lead to eventual resistance and cancer progression. Resistance has been associated with the induction of TP53 mutations, rendering MDM2 / MDMX / p53 complex inhibitors relatively useless (2-7). What is more, these inhibitors are unable to exploit p53-independent MDM2 / MDMX functions. 008849002

[0010] 2

[0011] Though this is an area of research that remains in its infancy, MDM2 homo- and heterodimers possess significant pro-oncogenic functions independent of p53 (2-7). In particular, studies assessing the specific functions of the RING / C-terminal dimerisation interface (DIF) of MDM2 / MDMX have highlighted the therapeutic potential of inhibiting MDM2 homo / hetero-dimerisation as an alternative approach to inhibiting MDM2 / MDMX pro-oncogenic activity, independent of TP53 mutational status (8-12).

[0012] Thus, therapeutic approaches capable of targeting a wider range of MDM2 / MDMX functions could have broader applications in cancer progression irrespective of TP53 mutational status. Suitable agents could also find utility in other indications in which MDM2 dimerisation has been implicated, such as in inflammatory and autoimmune disorders.

[0013] There is thus a need for further inhibitors of MDM2 dimerisation.

[0014] Summary of the Invention

[0015] The present invention provides an MDM2 inhibitor, comprising a disruptor component P which is capable of inhibiting MDM2:MDM2 homodimerisation and / or MDM2:MDMX heterodimerisation, wherein said disruptor component P is a peptide of at least 12 and no more than 20 residues in length, comprising

[0016] (i) a core sequence

[0017] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D or retro-inverso form thereof;

[0018] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2) or a retro-inverso form thereof;

[0019] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3) or a retro-inverso- form thereof;

[0020] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0021] (iii) a peptoid or N-methyl version of (i) or (ii). 008849002

[0022] 3

[0023] The core peptides having the sequences of SEQ ID NOs: 1 to 3 are analogues of residues 479-490 of wild type human MDM2 sequence. In each case, the individual positions within disruptor component P can be numbered linearly from 1 to 12, or alternatively can be given the numbering of the corresponding position from 479 to 490 within the MDM2 sequence, as determined by their alignment with that portion of the wild type MDM2 sequence, as follows:

[0024] Additional residues N-terminal of the core sequence may be numbered 0, -1 , -2, etc. in an N-terminal direction. Additional residues C-terminal of the core sequence may be numbered 13, 14, 15, etc, in a C- terminal direction. It may be desirable that any additional residues are only N-terminal of the core sequence, e.g. up to 5 residues, 4, 3, 2 or 1 residue upstream of the core sequence.

[0025] For convenience and consistency, linear numbering will be used in this specification where possible.

[0026] Without wishing to be bound by any particular theory, it is believed that the residues at positions 1 , 11 and 12 (corresponding to 479, 489 and 490) may be particularly important for interaction with MDM2 or MDMX and so for inhibiting homodimerisation or heterodimerisation. Consequently, it may be desirable that P comprises:

[0027] Arg or D-Arg at position 1 , or an N-methyl or N-substituted glycine analogue thereof;

[0028] Tyr, Trp, Phe, Leu, He or Vai at position 11 , or a D-form, N-methyl or N-substituted glycine analogue thereof; and / or

[0029] Phe, Trp, Tyr, Leu, He or Vai at position 12, or a D-form, N-methyl or N-substituted glycine analogue thereof.

[0030] P may comprise one, two or all three of those options.

[0031] Preferably P includes all three of:

[0032] Arg or D-Arg at position 1 , or an N-methyl or N-substituted glycine analogue thereof; 008849002

[0033] 4

[0034] Tyr, Trp, Phe, Leu, He or Vai at position 11 , or a D-form, N-methyl or N-substituted glycine analogue thereof; and

[0035] Phe, Trp, Tyr, Leu, He or Vai at position 12, or a D-form, N-methyl or N-substituted glycine analogue thereof.

[0036] Typically, the side chains of these residues are not involved in cyclisation, dimerisation, or conjugation to other moieties (such as a membrane transit moiety Z, as described in more detail below), so as not to interfere with their ability to interact with MDM2 or MDMX.

[0037] In some embodiments, position 9 of the core sequence (e.g,, Leu) may be substituted with other canonical or non-canonical hydrophobic amino acids. For example, Gly, Ala, Vai, lie, Pro, Met, Phe, Trp, methyl-phenylalanine, or naphthalene. Without wishing to be bound by theory, it is anticipated that substituting position 9 of the core sequence with other canonical or non-canonical hydrophobic residues may enhance protein binding.

[0038] An additional amino acid may be added to C-terminus of the core sequence (i.e., at position 13). The additional amino acid may be a canonical or non-canonical residue comprising an aromatic ring. Nonlimiting examples include Phe, Tyr, and Trp. Without wishing to be bound by theory, it is anticipated that the addition of a further amino acid at position 13 with a canonical or non-canonical residue comprising an aromatic ring may enhance protein binding.

[0039] The residues at positions 4 and 7 (corresponding to 482 and 485 of MDM2) or at positions 4 and 8 (corresponding to 482 and 486) may be selected such that their side chains are capable of forming a covalent bond. A pair of residues whose side chains participate in a covalent bond may be designated and *P. Thus the residues present at positions 4 and 7 (corresponding to 482 and 485) or at positions 4 and 8 (corresponding to 482 and 486) may be a pair of residues and ‘P whose side chains participate in a covalent bond.

[0040] The residues <5 and V may be any suitable pair of residues whose side chains are capable of forming an appropriate type of covalent bond. Examples include a disulfide bond, a thioether bond, and an amide (lactam) bond. An alternative arrangement would be an “all hydrocarbon” bond formed between two residues each having a side chain with a terminal alkene group, via a ring-closing metathesis (RCM) reaction. Other examples include, a triazole bridge or a scaffold bridge.

[0041] A disulfide bond may be formed between the side chains of two thiol-containing residues, such as cysteine or homocysteine. Thus and MJ may be Cys or homoCys; for example <P and 'P may both be Cys.

[0042] An amide (lactam) bond is typically formed between a side chain having a carboxylic acid functional group (e.g. Asp, Glu or Aad) and a side chain having an amine functional group (e.g. Dap, Dab, Orn, Lys or hLys). Thus one of <t> and * may be a residue with a side chain having a carboxylic acid functional 008849002

[0043] 5 group (e.g. Asp, Glu or Aad) and the other may be a residue with a side chain having an amine functional group (e.g. Dap, Dab, Orn, Lys or hLys).

[0044] A thioether bond may be formed in a number of different ways, e.g. between a pair of thiol-containing side chains (such as cysteine or homocysteine) to form a thioether rather than a disulfide, between a side chain having a thiol group (such as cysteine or homocysteine) and a side chain having a hydroxyl group (such as serine or threonine), or between a side chain containing a thiol group (such as cysteine or homocysteine) and a side chain containing a halomethylene group, such as a side chain containing a chloromethylene group (such as chloroalanine, or a side chain containing a chloroacetyl group), a bromomethylene group (such as bromoalanine, or a side chain containing a bromoacetyl group), or an iodomethylene group (such as iodoalanine, or a side chain containing an iodoacetyl group). The same structure (a lanthionine bridge; 3,3-thiodialanine) is formed e.g. between a pair of cysteine side chains, between a cysteine side chain and a serine side chain, or between a cysteine side chain and a betachloro alanine side chain. Alternatively, a cystathionine bridge may be formed between a homocysteine side chain and a serine side chain or a chloroalanine side chain. Thus one of and MJ may be Cys or homoCys and the other may be Cys, homoCys, Ser, Thr or beta-choro alanine. For example, one of <D may be Cys and the other may be Cys, Ser or beta-choro alanine.

[0045] A triazole bridge may be used as an alternative to a disulphide bridge. They are associated with chemical stability to proteases, isomerases and reducing agents. The formation of triazole bridges may be based on click chemistry between an azide functionalised amino acid and an alkynyl functionalised amino acid. Thus, one of $ and * may be Pra and the other may be Abu(N3) or Nva(N3). In some embodiments, one of <5 and is Pra and the other is Abu(N3). In further embodiments, is Pra and *P is Abu(N3). Without wishing to be bound by theory, it is anticipated that depending on the type of catalyst used in the reaction, the triazole bridges can be 1 , 4-disubstituted 1 , 2, 3-triazole, using copper (I) as a catalyst, or 1 , 5-disubstituted 1 , 2, 3-triazoles, using ruthenium (ll)-based catalysts. Either may be suitable for the purposes of the invention. 1, 4-disubstituted 1 , 2, 3-triazole may be preferred in some embodiments.

[0046] Alternatively, small rigid molecular scaffolds may be used to induce peptide cyclisation. Without wishing to be bound by theory, the technology relies on reacting thiols, typically from cysteine residues in the peptide sequences, with the scaffold to form stable, covalent thioether bond between the amino acid residue and the scaffold. Thus, one of <t> and '+’ may be Cys or homoCys and the other may be Cys or homoCys. In some embodiments, one of ct> and *P is Cys and the other is Cys. In some embodiments, the peptide is cyclised via a scaffold which comprises an aryl and / or a heteroaryl ring. The scaffold may react to link the side chains of the residues. The aryl ring may be a C5-C20 aryl and may be fused or unfused. The heteroaryl ring may include 5 to 20 ring atoms and may be fused or un-fused. The heteroaryl ring may include 1-3 heteroatoms independently selected from O, N and S. In some embodiments, the scaffold comprises a plurality of aryl and / or heteroaryl rings. In some embodiments, the aryl ring is a Ce, C10 or C14 aryl ring. In some embodiments, the heteroaryl ring includes 6 ring atoms. In some embodiments, the heteroaryl ring comprises a nitrogen ring atom. In some embodiments, the scaffold, in un-reacted form, includes at least two functional groups capable of forming a thioether bond with, for 008849002

[0047] 6 example, a cysteine residue. In some embodiments, each functional group is independently a leaving group or other labile chemical moiety. In some embodiments each functional group is independently a halogen leaving group, for example a Cl, Br or I leaving group. In some embodiments, the scaffold in unreacted form is 1 ,2-bis(bromomethyl)benzene, 1 ,3-bis(bromomethyl)benzene, or 1 ,4- bis(bromomethyl)benzene, and therefore upon peptide cyclisation, the scaffold forms a 1 ,2- di(methyl)benzene unit, a 1 ,3-di(methyl)benzene unit or a 1 ,4-di(methyl)benzene unit between sulphur atoms. In some embodiments, the scaffold in unreacted form is 2,6-bis(bromomethyl)pyridine, and therefore upon peptide cyclisation, the scaffold forms a 2,6-di(methyl)pyridine unit between sulphur atoms.

[0048] Residues having terminal alkene groups suitable for forming an “all hydrocarbon” bond include alphadisubstituted non-proteinogenic amino acids such as "R5" (i.e. (R)-2-Amino-2-methylhept-6-enoic acid), "S5" (i.e. (S)-2-Amino-2-methylhept-6-enoic acid), "R8" (i.e. (R)-2-Amino-2-methyldec-9-enoic acid) and "S8" (i.e. (S)-2-Amino-2-methyldec-9-enoic acid). Pairs of such residues are often used for stabilisation of alpha-helical structures (by so-called “peptide stapling”) but may also be appropriate for cyclisation in the context of the present invention. See Walensky and Bird, J. Med. Chem. 2014, 57, 6275-6288 (dx.doi.org / 10.1021 / jm4011675), as well as McDougall and Jamieson (Stapled Peptides as Potential Therapeutics. In: eLS. John Wiley & Sons, Ltd: Chichester. DOI: 10.1002 / 9780470015902.a0028403, March 2019) and references cited therein.

[0049] Alternatively, residues at positions 4 and 8 or residues 4 and 7 may be Aib. Without wishing to be bound by theory, it is believed that the addition of the amino acid Aib at these positions promotes helicity in structure.

[0050] The disruptor component P is a peptide of at least 12 and no more than 20 residues in length. For example, it may be no more than 19, no more than 18, no more than 17, no more than 16, no more than 15, no more than 14, no more than 13, or no more than 12 residues in length. In some embodiments, it is 12 to 15 residues in length, e.g. 12, 13, 14 or 15 amino acid residues in length. By “residue” is meant a residue of an amino acid (whether in L or D configuration, and including N-methylated amino acids) or a residue of an N-substituted glycine, as appropriate. Indeed an N-substituted glycine may itself be regarded as an amino acid residue.

[0051] The MDM2 inhibitor may comprise one or more heterologous moieties. For example, a heterologous moiety may be a membrane transit moiety or a pharmacokinetic-modifying moiety. Any given heterologous moiety may be peptidic or non-peptidic, and may be linked to the disruptor component P via a terminal backbone functional group of P (e.g. at the N-terminus) or via a side chain of P. Where the heterologous moiety is peptidic, it may form a continuous peptide chain (i.e. a fusion protein) with P.

[0052] Particularly when the heterologous moiety is peptidic, it may be desirable that the heterologous moiety is located N-terminal of the core sequence, so as not to interfere with binding between the C-terminal end of the core sequence and MDM2 or MDMX. It may be desirable that the heterologous moiety is spaced 008849002

[0053] 7 from the N-terminus of the core sequence by at least one amino acid, e.g. by one to five amino acids, which may be numbered 0, -1 , -2, etc., as appropriate. Such amino acids may be considered as a linker peptide.

[0054] When a heterologous moiety is linked to a side chain of P, the residue of P to which it is linked may be designated . may be present at any appropriate position of P. Any residue having an appropriate side chain functional group for attachment may be used at the relevant position of P. The side chains of Ser, Cys, homocysteine (hCys), Lys or Gin and D-forms thereof may be especially appropriate.

[0055] Positions 2, 3, 4 and 9 (corresponding to Gin 480, Pro 481 , He 482 and Vai 486) may be particularly suitable for a residue Position 9 may be particularly preferred. When a heterologous moiety is present at one of these positions, it may be desirable that it is a non-peptide heterologous moiety, such as a polymeric or lipophilic moiety as described in more detail below.

[0056] Alternatively, a residue may be present at position 0, or further N-terminal. Thus the disruptor peptide P may comprise a residue at position 0, wherein the heterologous moiety is linked to the side chain of the residue Without wishing to be bound by theory, it is believed that a greater variety of heterologous moieties can be accommodated at such a position. Thus, when located at position 0 (or further N- terminal) the heterologous moiety may be a peptide or non-peptide heterologous moiety, including a membrane transit moiety such as a cell penetrating peptide. In some embodiments, the residue at such a position may be Cys, hCys, or a D-form of either.

[0057] The heterologous moiety is typically covalently linked to the disruptor component P. Linkage may be direct or via a linker moiety.

[0058] The MDM2 inhibitor may comprise more than one heterologous moiety, e.g. two or even three such moieties. For example, it may comprise a membrane transit agent in combination with a half-life extending moiety. However, it may be desirable that a given MDM2 inhibitor comprises a maximum of one heterologous moiety (and thus only one residue

[0059] A membrane transit moiety is a moiety which promotes transit of the disruptor component P across the plasma membrane of a target cell.

[0060] As noted above, a membrane transit moiety may be covalently linked to the disruptor component P, i.e. the membrane transit moiety is a component of the MDM2 inhibitor molecule. The membrane transit moiety may also be referred to as a cell penetrating moiety.

[0061] Thus the MDM2 inhibitor may comprise a disruptor component P and a cell penetrating moiety Z. P and Z are covalently linked. For example, Z may be linked to a side chain of P, or to the N- or C-terminus of P. Linkage may be direct, or via a linker or spacer moiety. 008849002

[0062] 8

[0063] The cell penetrating moiety Z may be a peptide. Such peptides are sometimes referred to as a cell penetrating peptide (CPP) or protein transduction domain (PTD). Such peptides are typically 5 to 30 amino acids in length, and typically carry an overall positive charge or are composed entirely of residues with non-polar and / or hydrophobic side chains. They are sometimes categorised as cationic (often characterised by high arginine content), amphipathic (often having high lysine content) or hydrophobic (composed of hydrophobic and non-polar residues).

[0064] Examples of CPPs include:

[0065] GRKKRRQRRRPPQ or GRKKRRQRRR (Tat) RQIKIWFQNRRMKWKK (Penetratin) RKKRRRESRKKRRRES (DPV3) GRPRESGKKRKRKRLKP (DPV6) RVRVFWHIPRLT (ARF (19-31) KLALKLALKALKAALKLA (MAP) KETWWETWWTEWSQPKKKRKV (Pep-1) GALFLGFLGAAGSTMGAWSQPKKKRKV (MPG) VSALK (Bip4)

[0066] CSIPPEVKFNPFVYLI (C105Y)

[0067] GIGAVLKVLTTGLPALISWKRKRQQ (Melittin)

[0068] HGLASTLTRWAHYNALIRAF (gH625)

[0069] PLILLRLLRGQF (Pept 1 )

[0070] PLIYLRLLRGQF (Pept 2)

[0071] KLWMRWYSPTTRRYG (IVV-14)

[0072] GWTLNSAGYLLGKINLKALAALAKKIL (Transportan)

[0073] MGLGLHLLVLAAALQGAKKKRKV (lg(v))

[0074] KLALKLALKALKAALKLA (Amphiphilic model peptide)

[0075] LLIILRRRIRKQAHAHSK (pVEC)

[0076] RRIPNRRPRR (HRSV)

[0077] RLWMRWYSPRTRAYGC

[0078] GWTLNSAGYLLGKINLKALAALAKKIL poly-arginine (e.g. R4-R18, e.g. R4-R10, such as Rs or Rs)

[0079] GR(4-IO)Q (R-TAT)

[0080] RxWx (i.e. repeating units of Arg and Trp) where x is 3-9, e.g. x is 5.

[0081] Longer peptides may also be suitable, such as the cell-penetrating sequences derived from HOX D12 and HOX C12 described for example in WO 2020 / 163771 :

[0082] ARKKRKPYTKQQIAELENEFLVNEFINRQKRKELSNRLNLSDQQVKIWFQNRRMKKKRVV (HOX D12; also known as CellPorter®);

[0083] SRKKRKPYSKLQLAELEGEFLVNEFITRQRRRELSDRLNLSDQQVKIWFQNRRMKKKRLL (H0X C12); 008849002

[0084] 9 and functional fragments and derivatives thereof.

[0085] See for example, Derakhshankhah and Jafari, Biomedicine & Pharmacotherapy 108 (2018) 1090-1096 and Xie at al., Front. Pharmacol., 20 May 2020, Sec. Experimental Pharmacology and Drug Discovery, https: / / doi.org / 10.3389 / fphar.2020.00697.

[0086] Functional fragments or variants of these peptides which retain cell penetrating activity may also be used.

[0087] For example, variants may contain one or more substitutions compared to the sequences shown.

[0088] Substitutions with D-equivalents of the original amino acids may be particularly desirable. All-D or retro- inverso forms may also be employed.

[0089] Cyclic versions of any of the above sequences may be particularly useful, and may be indicated by the notation “[cyclo]” or “cCPP”. They may have increased stability in vivo (e.g. in plasma) as compared to the linear versions. Examples include cyclo[GRKKRRQRRR] and cyclo[Grkkrrqrrr]. Cyclisation may be achieved by any appropriate means, as described elsewhere in this specification, although head-to-tail cyclisation may be preferred. Head-to-tail cyclisation may be indicated by asterisks “*” at the N- and C- terminal residues, e.g. G*RKKRRQRRR* and G*rkkrrqrrr*. Other example cyclic CPPs are “C12 cyclic CPP-K”

[0090] “C12 cyclic CPP-G 008849002

[0091] 10

[0092] In some embodiments, the CPP is C12-r-r-r-r, C12-r-r-r, C12-R-R-R-R or C12-R-R-R. C12 is 12 carbon alkyl chain (for example as depicted in the schematic above), “r” is D-Arg and “R” is L-Arg. In some embodiments, one of C12-r-r-r-r, C12-r-r-r, C12-R-R-R-R or C12-R-R-R is directly linked to the core sequence via a bond (e.g., in the form Z-L-P, as described below). A non-limiting example is C12-r-r-r-r-r- Q-P-Pra-Q-r-l-AbuN3-L-T-l-f-NH2, where “r-Q-P-Pra-Q-r-l-AbuN3-L-T-l-f” represents the core sequence.

[0093] Particularly useful examples include poly-arginine and poly-D-arginine, e.g. Arg4-is, [D-Arg]4-is, Arg4-io, [D- Arg]4-io, e.g. Args, Args, [D-Arg]s and [D-Arg]s, and the peptides GRKKRRQRRR, Grkkrrqrrr, cyclo[GRKKRRQRRR] and cyclo[Grkkrrqrrr], e.g. GRKKRRQRRR, Grkkrrqrrr, G*RKKRRQRRR* and G*rkkrrqrrr*.

[0094] The cell penetrating moiety may comprise or consist of any of the above.

[0095] Peptoid equivalents of any of the CPPs described herein may also be employed.

[0096] Alternatively, the cell penetrating moiety Z may be a non-peptide moiety. Non-peptide cell penetrating moieties are typically hydrophobic moieties which are able to be inserted into the plasma membrane of a target cell, e.g. fatty acids (such as stearic (octadecanoic) acid, palmitic (hexadecanoic) acid, myristic (tetradecanoic) acid, lauric (dodecanoic) acid, capric (decanoic) acid, caprylic (octanoic) acid, tannic acid, and lipids such as steroids, e.g. cholesterol).

[0097] The cell penetrating moiety Z may be linked to a side chain of one of the residues of P. It may be attached to the N-terminal amino group of P. 008849002

[0098] 11

[0099] Where the cell penetrating moiety Z is a peptide (or peptoid), it may be attached to P via a functional group of a side chain of Z, or via a functional group at the N- or C-terminus of the backbone of Z, if available (e.g. via the N-terminal amino group). Thus, for example, the linear peptides GRKKRRQRRR and Grkkrrqrrr may be attached via the backbone amino group of the N-terminal glycine residue.

[0100] Attachment via a backbone functional group will not be possible if Z is cyclised head-to-tail, but will be feasible for linear peptides Z and for peptides Z cyclised via residue side chains. Where attachment is via a side chain functional group of Z, any suitable side chain may be utilised. For example, the cyclic peptides cyclo[GRKKRRQRRR] and cyclo[Grkkrrqrrr] (e.g. G*RKKRRQRRR* and G*rkkrrqrrr*) may be attached via the glutamine (Q or q) side chain. A peptide Z may include a residue (such as a Cys or dCys residue) at the N- or C-terminus for this purpose, so as not to interfere with the cell penetrating activity of the rest of the peptide.

[0101] A terminal functional group of P or Z may be derivatised to provide an alternative functional group for reaction with the other one of P or Z.

[0102] For example, a moiety containing a halomethylene group may be introduced at the N-terminus of one of P or Z, and form a thioether bond with a thiol-containing side chain, such as a Cys side chain, in the other one of P or Z. Examples of suitable moieties include chloroacetyl, bromoacetyl and iodoacetyl, such as chloroacetyl. The MDM2 inhibitor may comprise P or Z having an N-terminus that is derivatised with a moiety containing a methylene group, which is attached to the other one of P or Z via a thioether bond at a thiol-containing side chain. For example, where Z is a linear peptide, the MDM2 inhibitor may comprise a group (*-C(=O)CH2-**) where * represents the point of attachment of the N-terminus of Z, and ** represents a cysteine residue in P. Alternatively, the MDM2 inhibitor may comprise a group (*-C(=O)CH2-**) where * represents the point of attachment of the N-terminus of P, and ** represents a cysteine residue in Z.

[0103] Linkage of Z to P may be by direct reaction of the relevant functional groups. Alternatively, linkage may occur via linker or spacer moieties, such as bifunctional linker groups.

[0104] Z may be linked to P via a linker moiety. A linker moiety is a divalent moiety in which the two free valencies each form part of a single bond to an adjacent atom. A linker moiety may comprise one or more groups selected from: polyalkyleneglycol, such as polyethylene glycol (PEG) and polypropylene glycol; an optionally substituted alkylene, such as optionally substituted C1-20 alkylene, such as optionally substituted C1-12 alkylene, such as optionally substituted C1-6 alkylene. ether (-O-); thioether (-S-); amino (-N(H)-); amide, which may be represented by (-N(RN)-C(=O)-) or (-C(=O)N(RN)-); ester, which may be represented by (-OC(=O)-) or (-C(=O)O-); 008849002

[0105] 12 carbonyl (-C(=O)-); carbamate, which may be represented by (-OC(=O)N(RNA)-) or (-N(RNA)C(=O)O-), carbonate (-OC(=O)O-); and urea (-N(RNB)C(=O)N(RNC)-).

[0106] RN, RNA, RNBand RNCmay each independently be selected from hydrogen, Ci-e alkyl, Cs-2o aryl and C5-20 heteroaryl. Preferably, RN, RNA, RNBand RNCare each independent selected from hydrogen and C1-6 alkyl; such as hydrogen, methyl and ethyl; such as hydrogen.

[0107] Where two or more groups are present in the linker at least one of these groups may be alkylene. Where two or more groups selected from ether, thioether, amino, amide, ester, carbonyl, carbamate, carbonate and urea are present, these groups may be separated by alkylene. Thus, where two or more groups selected from ether, thioether, amino, amide, ester, carbonyl, carbamate, carbonate and urea are present, these groups are typically not directly connected to each other.

[0108] Where an alkylene group is substituted, the substituent may be one or more groups selected from an amido group, such as a formamidyl group (-C(=O)NH2); an ester group, such as (-C(=O)OMe) or (-C(=O)OEt); an acyl group, such as formyl (-C(=O)H) or acetyl (-C(=O)Me); and a carboxy group (-C(=O)OH).

[0109] A linker moiety may comprise an amino group, an alkylene group and a carbonyl group, such as a linker moiety derived from 6-aminohexanoic acid (Ahx).

[0110] Preferably, a linker moiety comprises one or more of a polyethylene glycol, an amide and an optionally substituted alkylene group. An optionally substituted alkylene group, where present, may be substituted with an amido group, such as a formamidyl group.

[0111] A linker moiety may comprise a methylene group and a carbonyl group, such as wherein the linker comprises a group represented by (-C(=O)-CH2-). In these embodiments, the linker moiety may be attached, such as via the methylene group, to a thiol-containing side chain, such as a cysteine side chain.

[0112] A linker moiety may be covalently attached to P or Z at an N-terminal or C-terminal functional group or at an amino acid residue side chain, such as a glutamine (Q or q) side chain. Preferably, a linker moiety is connected at one end to a side chain in one of P or Z, such as the amino group in the side chain of a glutamine residue (Q or q). The linker moiety may be connected at the other end to an N-terminal or C- terminal functional group, or a side chain, of the other one of P or Z, preferably an N-terminal functional group or a side chain, more preferably the N-terminal amino group or the amino group in the side chain of a glutamine (Q or q) residue. 008849002

[0113] 13

[0114] Where a linker moiety is attached to an N-terminal functional group of P or Z, this may be to an N-terminal amino group. Where a linker moiety is attached to the C-terminus of one of P or Z, this may be to the C- terminal carbonyl group, such as to provide an amide or ester linkage.

[0115] Where P or Z comprises a free terminus which is not involved in cyclisation or linkage to the other one of P or Z, the free terminus may be attached to, or derivatised to form, an end group. Examples at the C-terminus include an amide end group. Examples at the N-terminus include an acyl group, such as an acetyl group.

[0116] Additionally or alternatively, the MDM2 inhibitor may be linked to a pharmacokinetic-modifying moiety, for example, in order to increase solubility and / or half-life in vivo (e.g. in plasma) and / or bioavailability. Such modification is also known to reduce clearance (e.g. renal clearance) of therapeutic proteins and peptides.

[0117] A pharmacokinetic-modifying moiety may comprise a polymeric or lipophilic moiety. Without wishing to be bound by theory, such a moiety may bind to albumin in the bloodstream, thus shielding the molecule from enzymatic degradation or clearance by the liver, which may enhance the half-life of the MDM2 inhibitor in vivo.

[0118] The polymeric moiety is preferably water soluble (amphiphilic or hydrophilic), non-toxic, and pharmaceutically inert. Suitable polymeric moieties include polyethylene glycol (PEG), homo- or copolymers of PEG, a monomethyl-substituted polymer of PEG (mPEG), or polyoxyethylene glycerol (POG). See, for example, Francis et al., (1998), Int. J. Hematology 68:1-18; Zalipsky (1995), Bioconjugate Chem. 6:150-165; and Delgado et al. (1992), Crit. Rev. Therap. Drug Carrier Syst. 9:249- 304.

[0119] Other suitable polymeric moieties include poly-amino acids such as poly-lysine, poly-aspartic acid and poly-glutamic acid (see for example Gombotz, et al. (1995), Bioconjugate Chem., vol. 6: 332-351 ;

[0120] Hudecz, et al. (1992), Bioconjugate Chem., vol. 3, 49-57; Tsukada, et al. (1984), J. Natl. Cancer Inst., vol 73,: 721-729; and Pratesi, et al. (1985), Br. J. Cancer, vol. 52: 841-848).

[0121] The polymeric moiety may be straight-chain or branched. It may have a molecular weight of 500-40,000 Da, for example 500-10,000 Da, 1000-5000 Da, 10,000-20,000 Da, or 20,000-40,000 Da.

[0122] The polymeric moiety may be linked to a terminal group or to the side chain of any suitable residue, in the same way as a cell penetrating moiety.

[0123] Z1comprises a hydrocarbon chain having from 2 to 24 carbon (C) atoms, such as from 6 to 24 carbon atoms, e.g. 6 to 22 carbon atoms, e.g. 10 to 22 C atoms, e.g. 10 to 20 C atoms. Preferably, it has at least 6 C atoms, and preferably it has 20 C atoms or fewer, e.g. 18 C atoms or fewer. For example, the hydrocarbon chain may contain 6, 8, 10, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. For example, 008849002

[0124] 14 it may contain 8, 10 or 12 carbon atoms.

[0125] Thus the lipophilic moiety may comprise or consist of a group CH3-(CH2)o-22-(CO)-, e.g. CH3-(CH2)4-22- (CO)-, e.g. CH3-(CH2)4-2O-(CO)-, e.g. CH3-(CH2)6-22-(CO)-, e.g. CH3-(CH2)6-2o-(CO)-.

[0126] For example, it may comprise or consist of a group selected from acetyl, hexanoyl, octanoyl, decanoyl, dodecanoyl, tetradecanoy I, hexadecanoyl, octadecanoyl and eicosanoyl, preferably octanoyl, decanoyl, dodecanoyl, hexadecanoyl, octadecanoyl or eicosanoyl, more preferably octanoyl, decanoyl, dodecanoyl.

[0127] Alternative such groups are derived from long-chain saturated a, co-di carboxylic acids of formula HOOC- (CH2)O-2^COOH.

[0128] Thus the lipophilic moiety may comprise or consist of a group HOOC-(CH2)o-22-(CO)-, e.g. HOOC-(CH2)4-22-(CO)-, e.g. HOOC-(CH2)4-2O-(CO)-, e.g. HOOC-(CH2)6-22-(CO)-, e.g. HOOC-(CH2)6-2o-(CO)-.

[0129] For example, the lipophilic moiety may comprise or consist of:

[0130] 5-carboxypentanoyl, i.e. HOOC-(CH2)4-(CO)-;

[0131] 7-carboxyheptanoyl, i.e. HOOC-(CH2)e-(CO)-;

[0132] 9-carboxynonanoyl, i.e. HOOC-(CH2)s-(CO)-;

[0133] 11-carboxyundecanoyl, i.e. HOOC-(CH2)IO-(CO)-;

[0134] 13-carboxytridecanoyl, i.e. HOOC-(CH2)i2-(CO)-;

[0135] 15-carboxypentadecanoyl, i.e. HOOC-(CH2)i4-(CO)-;

[0136] 17-carboxyheptadecanoyl, i.e. HOOC-(CH2)ie-(CO)-;

[0137] 19-carboxynonadecanoyl, i.e. HOOC-(CH2)IS-(CO)-; or

[0138] 21-carboxyheneicosanoyl, i.e. HOOC-(CH2)2o-(CO)-.

[0139] The core sequence may have the formula:

[0140] X1 -X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12 wherein

[0141] X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[0142] X2 is selected from Gin, Phe, Tyr, Leu, He, Gly, Met, Cys, His, Thr, Pro, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0143] X3 is selected from Pro, Gly, Cys, His, Thr, Gin, Asn and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or a residue

[0144] X4 is selected from He, Trp, Phe, Tyr, Leu, Vai, Gly, Met, Cys, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof, Aib, or is a residue <P or 008849002

[0145] 15

[0146] X5 is selected from Gin, Trp, Phe, Leu, He, Vai, Met, His, Thr, Pro, Ser and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0147] X6 is selected from Met, Tyr, Leu, He, Vai, Gly, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N- substituted glycine analogue thereof;

[0148] X7 is selected from lie, Phe, Tyr, Leu, Vai, Met, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0149] X8 is selected from Vai, Trp, Phe, Tyr, Leu, lie, Gly, Met, Cys, His, Thr, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, Aib, or is a residue MJ;

[0150] X9 is selected from Leu, Trp, Phe, Tyr, lie, Vai, Gly, Met, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0151] X10 is selected from Thr, Phe, Leu, lie, Vai, Gly, Met, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0152] X11 is selected from Tyr, Trp, Phe, Leu, lie, Vai, Gly, Met, Cys, His, Thr, Pro, Gin, Asn, Ser, Glu, Arg and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0153] X12 is selected from Phe, Trp, Tyr, Leu, lie, Vai, Gly, Met, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue and vice versa, a maximum of one residue is present, and, when present, the side chains of residues <D and 4* form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[0154] (i)

[0155] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;

[0156] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0157] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[0158] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0159] (iii) a peptoid, N-methyl or retro-inverso version of (i) or (ii).

[0160] In some embodiments:

[0161] X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[0162] X2 is selected from Gin, Phe, Tyr, Leu, lie, Gly, Met, Cys, His, Thr, Pro, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[0163] X3 is selected from Pro, Gly, Cys, His, Thr, Gin, Asn and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue 008849002

[0164] 16

[0165] X4 is selected from He, Trp, Phe, Tyr, Leu, Vai, Gly, Met, Cys, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof, Aib, or is a residue or

[0166] X5 is selected from Gin, Trp, Phe, Leu, He, Vai, Met, His, Thr, Pro, Ser and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0167] X6 is selected from Met, Tyr, Leu, lie, Vai, Gly, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N- substituted glycine analogue thereof;

[0168] X7 is selected from lie, Phe, Tyr, Leu, Vai, Met, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue *;

[0169] X8 is selected from Vai, Trp, Phe, Tyr, Leu, lie, Gly, Met, Cys, His, Thr, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, Aib, or is a residue MJ;

[0170] X9 is selected from Leu, Trp, Phe, Tyr, lie, Vai, Gly, Met, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[0171] X10 is selected from Thr, Phe, Leu, lie, Vai, Gly, Met, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0172] X11 is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;

[0173] X12 is selected from Phe, Trp, Tyr, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue ct> then residue X7 or X8 is a residue and vice versa, a maximum of one residue is present, and, when present, the side chains of residues <t> and MJ form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[0174] (i)

[0175] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;

[0176] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0177] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[0178] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0179] (iii) a peptoid, N-methyl or retro-inverso version of (i) or (ii).

[0180] In some embodiments:

[0181] X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[0182] X2 is selected from Gin, Gly, His, Thr, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue 008849002

[0183] 17

[0184] X3 is selected from Pro, Gly and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[0185] X4 is selected from He, Trp, Tyr, Leu, Vai, Gly, His, Thr, Gin and Ser, or a D-form, N-methyl, or N- substituted glycine analogue thereof, Aib, or is a residue or

[0186] X5 is selected from Gin, His, Thr and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0187] X6 is selected from Met, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0188] X7 is selected from He, Phe, Tyr, Leu, Vai, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue 4J;

[0189] X8 is selected from Vai, Phe, Tyr, Leu, lie, Thr, Asn, Ser, Asp and Glu, or a D-form, N-methyl, or N- substituted glycine analogue thereof, Aib, or is a residue

[0190] X9 is selected from Leu, Phe, Tyr, lie, Vai, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[0191] X10 is selected from Thr, Gly, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0192] X11 is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;

[0193] X12 is selected from Phe, Trp, Tyr, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue <5 then residue X7 or X8 is a residue and vice versa, a maximum of one residue is present, and, when present, the side chains of residues and form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[0194] (i)

[0195] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;

[0196] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0197] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[0198] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0199] (iii) a peptoid, N-methyl version or retro-inverso form of (i) or (ii).

[0200] In some embodiments:

[0201] X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof; 008849002

[0202] 18

[0203] X2 is selected from Gin, Gly, His, Thr, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0204] X3 is selected from Pro, Gly and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[0205] X4 is selected from He, Gly, His, Thr, Gin and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof, Aib, or is a residue <P or

[0206] X5 is selected from Gin, His, Thr and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0207] X6 is selected from Met, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0208] X7 is selected from He, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ^P;

[0209] X8 is selected from Vai, Thr, Asn, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, Aib, or is a residue ^P;

[0210] X9 is selected from Leu, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0211] X10 is selected from Thr, Gly, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0212] X11 is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;

[0213] X12 is selected from Phe, Trp, Tyr, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue cP then residue X7 or X8 is a residue and vice versa, a maximum of one residue is present, and, when present, the side chains of residues <P and form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[0214] (i)

[0215] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;

[0216] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0217] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[0218] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0219] (iii) a peptoid, N-methyl version or retro-inverso form of (i) or (ii). 008849002

[0220] 19

[0221] The core sequence may have the formula:

[0222] X1-Gln-Pro-X4-Gln-X6-X7-X8-X9-Thr-X11-X12 where

[0223] XI is selected from Arg and D-Arg

[0224] X4 is He, or is a residue

[0225] X6 is selected from Met and Thr, or a D-form thereof;

[0226] X7 is He, or is a residue MJ;

[0227] X8 is Vai, or is a residue MJ;

[0228] X9 is Leu, or is a residue

[0229] XI I is selected from Tyr and Leu, or a D-form thereof;

[0230] X12 is selected from Phe and D-Phe.

[0231] Alternatively, the core sequence may have the formula:

[0232] X1-Gln-Pro-X4-Gln-X6-X7-X8-X9-Thr-X11-X12 where

[0233] XI is selected from Arg and D-Arg

[0234] X4 is lie, Gin, Aib, or is a residue

[0235] X6 is selected from Met and Thr, or a D-form thereof;

[0236] X7 is lie, or is a residue MJ;

[0237] X8 is Vai, Asp, Aib, or is a residue MJ;

[0238] X9 is Leu, or is a residue ;

[0239] XI I is selected from Tyr and Leu, or a D-form thereof;

[0240] X12 is selected from Phe and D-Phe.

[0241] In some embodiments, the core sequence may have the formula:

[0242] X1-Gln-Pro-X4-Gln-X6-X7-X8-X9-Thr-X11-X12-X13 where

[0243] X1 is selected from Arg and D-Arg, preferably D-Arg 008849002

[0244] 20

[0245] X4 is He, Gin, Aib, or is a residue or , preferably residue 0 (e.g., Pra);

[0246] X6 is selected from Met and Thr, or a D-form thereof, preferably D-Thr;

[0247] X7 is He, or is a residue ’+', preferably lie;

[0248] X8 is Vai, Asp, Aib, or is a residue1, preferably (e.g., AbuN3);

[0249] X9 is Leu, Gly, Ala, Vai, lie, Pro, Met, Phe, Trp, methyl-phenylalanine or naphthalene;

[0250] X11 is selected from Tyr and Leu, or a D-form thereof, preferably D-Leu;

[0251] X12 is selected from Phe and D-Phe, preferably D-Phe;

[0252] X13 is absent or Phe, Tyr or Trp.

[0253] In some embodiments, X9 is selected from the group consisting of Gly, Ala, Vai, lie, Pro, Met, Phe, Trp, methyl-phenylalanine, or naphthalene and / or X13 is selected from the group consisting of Phe, Tyr or Trp.

[0254] As noted above, the disruptor component P may comprise additional sequence N- or C-terminal of the core sequence. For example, it may comprise a residue , e.g. N-terminal of the core sequence, e.g. at position X0. The residue may be Cys, hCys, or a D-form of either. Cys may be preferred.

[0255] The disruptor component P may comprise more than one residue linked to a heterologous moiety, e.g. two or even three such moieties. For example, it may comprise a membrane transit agent in combination with a half-life extending moiety. However, typically, the disruptor component comprises a maximum of one residue

[0256] Examples of the core sequence include:

[0257] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1);

[0258] Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0259] [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; and

[0260] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe; or a peptoid, N-methyl or retro-inverso version thereof.

[0261] Other examples include: 008849002

[0262] 21

[0263] [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Asp-Leu-Thr-[D-Leu]-[D-Phe];

[0264] [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0265] [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Asp-Leu-Thr-[D-Leu]-[D-Phe]; and

[0266] [D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-Leu-Thr-[D-Leu]-[D-Phe]; or a peptoid, N-methyl or retro-inverso version thereof.

[0267] Further examples of the core sequence include:

[0268] Arg-GIn-Pro-cD-GIn-Met-lle-^P-Leu-Thr-Leu-Phe;

[0269] Arg-Gln-Pro-<t>-Gln-Met-lle-'4J-Leu-Thr-[D-Leu]-[D-Phe];

[0270] [D-Arg]-Gln-Pro-<D-Gln-[D-Thr]-lle-^-Leu-Thr-[D-Leu]-[D-Phe];

[0271] Arg-GIn-Pro-cD-GIn-Met-lle-^P-Leu-Thr-Tyr-Phe;

[0272] Arg-Gln-Pro-<D-Gln-Met-'P-Val-Leu-Thr-Leu-Phe;

[0273] Arg-Gln-Pro-<D-Gln-Met-'P-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0274] [D-Arg]-Gln-Pro-<D-Gln-[D-Thr]-iP-Val-Leu-Thr-[D-Leu]-[D-Phe]; and

[0275] Arg-Gln-Pro-d>-Gln-Met-'P-Val-Leu-Thr-Tyr-Phe; where the side chains of residues and *P form a covalent bond; or a peptoid, N-methyl or retro-inverso version thereof.

[0276] The pair of residues <D and *P may be any of the pairs of residues discussed above whose side chains are capable of forming a covalent bond. For example, the side chains of residues and ^P may form a disulfide bond, a thioether bond, an amide (lactam) bond, or an “all hydrocarbon” bond. Thus, and 'P may independently be Cys or homoCys; for example <D and *P may both be Cys. Alternatively, <U and *P may independently be R5, S5, R8 or S8, for example, <D and *P may both be S5. The side chains of residues and *P may form a triazole bridge. In such an example, may be Pra and *P may be Abu(N3). Alternatively, the side chains of residues <t> and ^P may be connected via a scaffold as described herein. For example, <U and *P may each be Cys and the scaffold may be a 1 ,4- bis(bromomethyl)benzene scaffold which upon peptide cyclisation, forms a 1 ,4-di(methyl)benzene unit between sulphur atoms. 008849002

[0277] 22

[0278] In some embodiments, the core sequence is selected from the group consisting of [D-Arg]-Gln-Pro-lle- Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] and [D-Arg]-Gln-Pro-Pra-Gln-[D-Thr]-lle-Abu(N3)-Leu-Thr-[D- Leu]-[D-Phe],

[0279] The disruptor component P may comprise a sequence selected from:

[0280] ^-Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe; -Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0281] <-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0282] ^-Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe;

[0283] Arg-GIn-Pro-lle-GIn-Met-lle-Val-^-Thr-Leu-Phe;

[0284] Arg-Gln-Pro-lle-Gln-Met-lle-Val-<-Thr-[D-Leu]-[D-Phe];

[0285] [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val- -Thr-[D-Leu]-[D-Phe]; and Arg-GIn-Pro-lle-GIn-Met-lle-Val-^-Thr-Tyr-Phe; where the side chain of the residue ( forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof.

[0286] Alternatively, the disruptor component P may comprise a sequence selected from:

[0287] <-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Asp-Leu-Thr-[D-Leu]-[D-Phe]; - [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0288] [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Asp-Leu-Thr-[D-Leu]-[D-Phe];

[0289] [D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-Leu-Thr-[D-Leu]-[D-Phe];

[0290] [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Asp-<-Thr-[D-Leu]-[D-Phe];

[0291] [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val- -Thr-[D-Leu]-[D-Phe];

[0292] [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Asp-<-Thr-[D-Leu]-[D-Phe]; and [D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib- -Thr-[D-Leu]-[D-Phe]; 008849002

[0293] 23 where the side chain of the residue ( forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof.

[0294] Further examples of the disruptor component P include:

[0295] ^-Arg-GIn-Pro-O-GIn-Met-lle-'+'-Leu-Thr-Leu-Phe;

[0296] <-Arg-Gln-Pro-O-Gln-Met-lle-^-Leu-Thr-[D-Leu]-[D-Phe];

[0297] <-[D-Arg]-Gln-Pro-ct>-Gln-[D-Thr]-lle-^-Leu-Thr-[D-Leu]-[D-Phe];

[0298] (-Arg-GIn-Pro-cb-GIn-Met-lle-^P-Leu-Thr-Tyr-Phe;

[0299] (-Arg-GIn-Pro-cb-GIn-Met-^P-Val-Leu-Thr-Leu-Phe;

[0300] <-Arg-Gln-Pro-0-Gln-Met-^-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0301] <-[D-Arg]-Gln-Pro-ct>-Gln-[D-Thr]-^-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0302] (-Arg-GIn-Pro-cb-GIn-Met-^P-Val-Leu-Thr-Tyr-Phe;

[0303] Arg-Gln-Pro-<t>-Gln-Met-lle-'4J-£-Thr-Leu-Phe;

[0304] Arg-Gln-Pro-<D-Gln-Met-lle-^-<-Thr-[D-Leu]-[D-Phe];

[0305] [D-Arg]-Gln-Pro-<D-Gln-[D-Thr]-lle-^-<-Thr-[D-Leu]-[D-Phe];

[0306] Arg-Gln-Pro-<t>-Gln-Met-lle-'4J-£-Thr-Tyr-Phe;

[0307] Arg-GIn-Pro-cb-GIn-Met-'+’-Val-^-Thr-Leu-Phe;

[0308] Arg-Gln-Pro-<D-Gln-Met-iP-Val-<-Thr-[D-Leu]-[D-Phe];

[0309] [D-Arg]-Gln-Pro-<b-Gln-[D-Thr]-MJ-Val <-Thr-[D-Leu]-[D-Phe]; and

[0310] Arg-GIn-Pro-O-GIn-Met-'+’-Val-^-Thr-Tyr-Phe; where the side chains of residues <t> and form a covalent bond; and where the side chain of the residue £ forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof. 008849002

[0311] 24

[0312] The residue may, for example, be a thiol-containing residue, e.g. Cys, hCys, D-Cys or D-hCys. Cys and D-Cys may be preferred.

[0313] The heterologous moiety may be a membrane transit moiety Z, e.g. non-peptide cell-penetrating moiety (e.g. a hydrophobic moiety such as a fatty acid or lipid) or a cell penetrating peptide. When the residue is a thiol-containing residue (Cys, hCys, or a D-form thereof) and the membrane transit moiety is a cell penetrating peptide, the N-terminus of the cell penetrating peptide may be linked to the side chain of the residue via a thioether link.

[0314] The pair of residues and *P may be any of the pairs of residues discussed above whose side chains are capable of forming a covalent bond. For example, the side chains of residues <D and ^P may form a disulfide bond, a thioether bond, an amide (lactam) bond, or an “all hydrocarbon” bond. Thus, and * may independently be Cys or homoCys; for example <D and may both be Cys. Alternatively, and * may independently be R5, S5, R8 or S8, for example, <P and may both be S5. The side chains of residues <P and *P may form a triazole bridge. In such an example, <P may be Pra and * may be

[0315] Abu(N3). Alternatively, the side chains of residues <P and 'P may be connected via a scaffold as described herein. For example, <P and ip may each be Cys and the scaffold may be a 1 ,4- bis(bromomethyl)benzene scaffold which upon peptide cyclisation, forms a 1 ,4-di(methyl)benzene unit between sulphur atoms.

[0316] In some embodiments, the disruptor component P comprises a sequence selected from the group consisting of -[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] and ^-[D-Arg]-Gln-Pro- Pra-Gln-[D-Thr]-lle-Abu(N3)-Leu-Thr-[D-Leu]-[D-Phe],

[0317] The MDM2 inhibitor may comprise, or may be, a peptide having the formula

[0318] Z-L-P where

[0319] Z is a cell penetrating peptide;

[0320] P is a disruptor component; and

[0321] L is a linker peptide sequence (e.g. of 1-10 amino acids, e.g. of 1-5 amino acids), or represents a bond between Z and P; or a peptoid, N-methyl or retro-inverso version thereof.

[0322] The MDM2 inhibitor may have the formula Y1-Z-L-P-Y2 008849002

[0323] 25 where

[0324] Y1 is H, Ac or a heterologous moiety (e.g. H or Ac);

[0325] Z is a cell penetrating peptide;

[0326] P is a disruptor component;

[0327] L is a linker peptide sequence (e.g. of 1-10 amino acids, e.g. of 1-5 amino acids), or represents a bond between Z and P; and

[0328] Y2 is OH, NH2 or a heterologous moiety (e.g. OH or NH2); or a peptoid, N-methyl or retro-inverso version thereof.

[0329] P may be any disruptor component as defined elsewhere in this specification.

[0330] Z may be any cell penetrating peptide, e.g. as defined elsewhere in this specification.

[0331] In such embodiments, since the MDM2 inhibitor contains a cell penetrating peptide as part of the peptide backbone, any heterologous moiety present at Y1 , Y2, or at any residue within the disruptor component is typically not a membrane transit moiety.

[0332] In some embodiments, the MDM2 inhibitor does not contain a heterologous moiety or any residue

[0333] Alternatively, the MDM2 inhibitor may have the formula

[0334] Y1-P-Y2 where

[0335] Y1 is H, Ac or a heterologous moiety;

[0336] P is a disruptor component; and

[0337] Y2 is OH, NH2 or a heterologous moiety (e.g. OH or NH2); or a peptoid, N-methyl or retro-inverso version thereof.

[0338] As discussed, it may be desirable that the MDM2 inihbitor comprises a membrane transit moiety. For example, in some embodiments, either Y1 or Y2 is a heterologous moiety which is a membrane transit moiety, or a membrane transit moiety is linked to a side chain of P at a residue t,. 008849002

[0339] 26

[0340] If desired, the disruptor component may be cyclised head-to-tail, i.e. between the terminal and groups of the peptide backbone. Such cyclisation may be direct, e.g. by formation of an amide bond between an N- terminal amine group and a C-terminal carboxyl group. Alternatively such cyclisation may be via a chemical linker between the terminal groups. In such embodiments the inhibitor will not contain Y1 or Y2 groups since they will instead constitute the bond cyclising the peptide, or bonds to the chemical linker group. Such head-to-tail cyclisation may be indicated by asterisks (“*”) at the N- and C-terminal amino acids of the sequence of P.

[0341] The MDM2 inhibitor may comprise:

[0342] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe;

[0343] (Stearoyl)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe;

[0344] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe;

[0345] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Tyr]-[D-Phe];

[0346] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Leu-Phe;

[0347] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0348] [D-Arg]8-Cys-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0349] Cys(-Ac-[D-Arg]9-NH2)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; or

[0350] [D-Cys](-Ac-[D-Arg]9-NH2)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; or a peptoid, N-methyl or retro-inverso version thereof.

[0351] The MDM2 inhibitor may be selected from:

[0352] Ac-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe-NH2;

[0353] (Stearoyl)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe-NH2 (DRx-97-S);

[0354] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe -NH2(DRx-97-R);

[0355] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Tyr]-[D-Phe]-NH2(DRx-97D-R);

[0356] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Leu-Phe-NH2 (DRx-98R);

[0357] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-98D-R);

[0358] Ac-[D-Arg]8-Cys-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-990);

[0359] Ac-Cys(-Ac-[D-Arg]9-NH2)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2 (DRx-991 ); and 008849002

[0360] 27

[0361] Ac-[D-Cys](-Ac-[D-Arg]9-NH2)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2 (DRx- 992); or a peptoid, N-methyl or retro-inverso version thereof.

[0362] The MDM2 inhibitor may comprise:

[0363] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe;

[0364] (Stearoyl)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe;

[0365] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe;

[0366] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Tyr]-[D-Phe];

[0367] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Leu-Phe;

[0368] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0369] [D-Arg]8-Cys-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0370] Cys(-Ac-[D-Arg]9-NH2)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0371] [D-Cys](-Ac-[D-Arg]9-NH2)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0372] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0373] Cys-(-C12-cCPP-C)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0374] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0375] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-Leu-Thr-[D-Leu]-[D-Phe];

[0376] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-hCys-Gln-[D-Thr]-lle-hCys-Leu-Thr-[D-Leu]-[D-Phe];

[0377] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Pra-Gln-[D-Thr]-lle-Abu(N3)-Leu-Thr-[D-Leu]-[D-Phe]; or

[0378] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Cys-Gln-[D-Thr]-lle-Cys-Leu-Thr-[D-Leu]-[D-Phe]; or a peptoid, N-methyl or retro-inverso version thereof.

[0379] The MDM2 inhibitor may be selected from:

[0380] Ac-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe-NH2;

[0381] (Stearoyl)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe-NH2 (DRx-97-S);

[0382] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe -NH2 (DRx-97-R);

[0383] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Tyr]-[D-Phe]-NH2(DRx-97D-R); 008849002

[0384] 28

[0385] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Leu-Phe-NH2 (DRx-98R);

[0386] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-98D-R);

[0387] Ac-[D-Arg]8-Cys-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-990);

[0388] Ac-Cys(-Ac-[D-Arg]9-NH2)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-991 );

[0389] Ac-[D-Cys](-Ac-[D-Arg]9-NH2)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx- 992);

[0390] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(7175);

[0391] Cys-(-C12-cCPP-C)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(7176);

[0392] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(1724);

[0393] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-Leu-Thr-[D-Leu]-[D-Phe]-NH2(1211 );

[0394] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-hCys-Gln-[D-Thr]-lle-hCys-Leu-Thr-[D-Leu]-[D-Phe]-NH2(3276);

[0395] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Pra-Gln-[D-Thr]-lle-Abu(N3)-Leu-Thr-[D-Leu]-[D-Phe]-NH2(3277); and

[0396] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Cys-Gln-[D-Thr]-lle-Cys-Leu-Thr-[D-Leu]-[D-Phe]-NH2(3275); or a peptoid, N-methyl or retro-inverso version thereof.

[0397] In some aspects of the invention, the MDM2 inhibitor comprises a dimeric disruptor component, where the two monomeric disruptor peptides are combined to form a dimeric disruptor peptide. The peptides may be dimerised by linking non-essential residues from each peptide chain (e.g., amino acids which are not at positions 1 , 11 and 12). For example, two non-essential residues (one in each peptide) may be replaced with Cys and / or hCys and linked via disulphide bonds formed via their side chains. Alternative linkages may used such as triazoles or scaffolds as described herein. In such cases the relevant amino acids needed to form those linkages would be employed. In other examples, the peptides could be dimerised by head to tail dimerisation. Without wishing to be bound by theory, it is anticipated that combining two monomeric disruptor peptides to form a dimeric peptide will allow for dual interaction with both MDM2 and MDMX (e.g., MDM2:MDM2 or MDM2:MDMX), thereby exploiting the dimerisation interface. In some embodiments, the core sequence of the peptide to be dimerised is selected from the group consisting of [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] and [D-Arg]-Gln-Pro- Pra-Gln-[D-Thr]-lle-Abu(N3)-Leu-Thr-[D-Leu]-[D-Phe]. The peptides may be homodimerised or heterodimerised, preferably homodimerised.

[0398] The invention further provides a pharmaceutically acceptable salt of a MDM2 inhibitor as described herein. 008849002

[0399] 29

[0400] The invention further provides a pharmaceutical composition comprising a MDM2 inhibitor as described herein.

[0401] The invention further provides a MDM2 inhibitor as described herein for use in a method of medical treatment.

[0402] The invention further provides a MDM2 inhibitor as described herein for use in the treatment of cancer, inflammatory disease, dementia or a neurodegenerative disease, nephropathy, or heart or cardiovascular disease.

[0403] The invention further provides a method of treating cancer, inflammatory disease, dementia or a neurodegenerative disease, nephropathy, or heart or cardiovascular disease, comprising administering an effective amount of a MDM2 inhibitor as described herein to an individual in need thereof.

[0404] The invention further provides the use of a MDM2 inhibitor as described herein in the manufacture of a medicament for the treatment of cancer, inflammatory disease, dementia or a neurodegenerative disease, nephropathy, or heart or cardiovascular disease.

[0405] The cancer may, for example, be neuroblastoma, a myeloproliferative neoplasm (e.g. polycythemia vera or myelofibrosis), leukaemia (e.g. acute myeloid leukaemia,) lung cancer, colorectal cancer, osteosarcoma, melanoma or pancreatic cancer.

[0406] The inflammatory disease may, for example, be an autoimmune disease, e.g. rheumatoid arthritis, systemic lupus erythaematosus (SLE), pancreatitis or gastritis.

[0407] The dementia or neurodegenerative disease may be, or may be associated with, for example, fragile X syndrome, Parkinson’s disease or Alzheimer’s disease.

[0408] The nephropathy may, for example, be autosomal dominant polycystic kidney disease, renal fibrosis or diabetic nephropathy.

[0409] The cardiovascular disease may, for example, be, myocardial infarction or atherosclerosis. 008849002

[0410] 30

[0411] Summary of the Figures

[0412] Embodiments and experiments illustrating the principles of the invention will now be discussed with reference to the accompanying figures in which:

[0413] Figure 1 : Identification of MDM2-derived core disruptor peptide sequence

[0414] (A) Purified GST - MDM2 (428-C), GST - MDMX (428-C) and GST proteins visualised via (LEFT) coomassie stain and (RIGHT) a-GST antibody immunostaining. (B) MDM2-(428-C)-GST protein overlay and GST protein only overlay (negative control) onto peptide array containing the latter 19 amino acids of MDM2, encompassing MDM2’s RING - C-terminal dimerisation interface (DIF), critical in both MDM2 homodimerisation and heterodimerisation with MDMX. Truncation of C-terminal Proline and N-terminal N472 - C478 increased MDM2 protein binding signal. L487 - F490 is a crucial MDM2 motif needed for the formation of H+bonds with key contact residues on MDM2 (e.g., N433, K454, G456, L458) and MDMX (e.g., D429, N432, R445, N448, R453, G455, L457). Data normalised to peptide with strongest MDM2 binding signal, given a value of 1 . (C) 12mer peptide R479-F490 represents a rational core binding sequence. Based on 3D co-crystal structure of MDM2:MDMX heterodimerisation (PDB: 5MNJ) this sequence (within the complete, bound MDM2 protein) is made up of random coil and p-strand secondary structure.

[0415] Figure 2: Characterisation of MDM2-derived core disruptor peptide sequence:

[0416] (A) Densitometry of MDM2-(428-C)-GST protein overlay onto peptide array containing MDM2 peptides having single amino acid substitutions compared to control peptide RQPIQMIVLTYF. The position to be substituted is shown across the top of the array, with the individual substituent amino acids shown down the left side. Results are normalised to the control peptide RQPIQMIVLTYF. (B) % binding values for selected peptides.

[0417] Figure 3: MDM2 / MDMX - Peptide Target Engagement.

[0418] (A) 11-point dose response of FITC-labelled peptides [0.05 - 3 pM] binding - GST-MDM2 (RING-CT) protein (RFU, 50 ng per well). (B) Normalised peptide - MDM2 binding curves (100% = peptide concentration in which maximal binding observed). (C) 11 -point dose response of DRx-097A and DRx- 098D [0.05 - 3 pM] binding - GST-MDMX (RING-CT) protein (RFU, 50 ng per well). N=4, MEAN ± SEM. Ns, not significant; One-way ANOVA

[0419] Figure 4: MDM2-derived disruptor peptides inhibit p53-driven MDM2 ubiquitination 008849002

[0420] 31

[0421] (A) Biochemical assay assessing the inhibitory capability of MDM2-derived DRx-peptide disruptors against p53-mediated MDM2 ubiquitination following treatment (1 Hr, 10 pM, N=2). Respective immunoblots were immunoassayed utilising a mouse monoclonal anti-p53 antibody (sc-126). (B) Dose response treatments (1 Hr, 0.001 - 25 pM) with MDM2 disruptor peptides: DRx-097-R, DRx-097D-R, DRx-098-R, DRx-098D-R, and DRx-097A-R (negative control knockout peptide). p53-mediated ubiquitination of MDM2 was normalised to respective vehicle treated control on same immunoblot (i.e. , % diff. of 100%). (C) Bar chart detailing dose-dependent inhibition of p53-mediated MDM2 ubiquitination - with respective IC50’s above (MEAN ± SEM, N=3).

[0422] Figure 5: Full MDM2-derived disruptor peptide library vs. U2-OS cancer cell viability

[0423] End-point (CellTiter Gio) cell viability of human U2-OS osteosarcoma cells were determined following 72 Hrs treatment (low serum - 2% FBS - conditions) with Vehicle (0.25% DMSO), [3 pM] negative control knock-out peptide DRx-097A-R, [3 pM] positive MDM2-p53 inhibitor control Idasanutlin or [3 pM] of DRx disruptor peptide within disruptor peptide library. Relative cell viability normalised to vehicle control (100%) (n=7, MEAN ± SEM). The table shows numerical values for % cell viability inhibition induced by each treatment arm. DRx-098D-R induced the most significant relative viability inhibition of U2-OS cells.

[0424] Figure 6: Confirmation of (A) HA-MDM2 (435-C) and (B) Myc-MDMX (428-C) truncate protein transient transfection in U2-OS cells via western immunoblotting analysis.

[0425] 48 Hrs transfection duration protocol was utilised for subsequent experiments utilising this model. Primary antibodies for HA-tag (A) and Myc-tag (B) were utilised to identify MDM2 / MDMX protein expression. GAPDH was immunoblotted for as a housekeeper protein control.

[0426] Figure 7: DRx-098D-R downregulates MDM2:MDMX heterodimer complex formation.

[0427] (A) Graph summarising proximity ligation signal (PLA signal) measured from the complex formation of full-length endogenous MDM2 and overexpressed truncated Myc-MDMX-{428-C} (RING to C-terminus) protein in human U2-OS osteosarcoma cells, following treatment with Vehicle (0.25% DMSO), DRx-097A- R [5 pM], DRx-098D-R [0.5 pM], DRx-098D-R [5 pM] for 4 hours. (B) Representative images of U2-OS cells. Grey represents nuclei. White signal(s) represent formation of MDM2-MDM2 homodimers. Ns, not significant, * P < 0.05; One-way ANOVA. #cells per treatment arm = 25-38, 63X Objective.

[0428] Figure 8: DRx-098D-R downregulates MDM2:MDM2 homodimer complex formation.

[0429] (A) Graph summarising proximity ligation signal (PLA signal) measured from the complex formation of full-length endogenous MDM2 and overexpressed truncated HA-MDM2-{435-C} (RING to C-terminus) protein in human U2-OS osteosarcoma cells, following treatment with Vehicle (0.25% DMSO), DRx-097A- 008849002

[0430] 32

[0431] R [5 pM], DRx-098D-R [0.5 pM], DRx-098D-R [5 pM] for 4 hours. (B) Representative images of U2-OS cells. Grey represents nuclei. White signal(s) represent formation of MDM2-MDM2 homodimers. Ns, not significant, * P < 0.05; One-way ANOVA. #cells per treatment arm = 26-72, 63X Objective.

[0432] Figure 9: RTCA xCELLigence growth analysis of DRx-098D-R vs. HCT116

[0433] Real-time analysis of DRx-098D-R vs. HCT116 human HCT116 colorectal cancer cells was measured over a 48 Hrs treatment period (measurements every 15 minutes, low - 2% FBS - serum conditions) following treatment with Vehicle (0.25% DMSO) or [0.001 - 5 pM] dose response of DRx-098D-R. Cell index was normalised to treatment time point and represented as a % difference of vehicle (100%). N=3, MEAN ± SEM.

[0434] Figure 10: DRx-098D-R induces cancer cell specific inhibition

[0435] (A) Endpoint (CellTiter Gio) cell viability of human HCT116 colorectal cancer cells were determined following 24 Hrs treatment (low serum - 2% FBS - conditions) with Vehicle (0.25% DMSO), [3 pM] negative control knock-out peptide DRx-097A-R, or [0.1 - 5 pM] dose response of DRx-098D-R. Relative cell viability normalised as a % difference of 100% vehicle control (N=3, MEAN ± SEM). Horizontal lines represent cell viability of vehicle treatment (100%) and DRx-097A-R treatment and growth IC50 (50% viability). (B) Relative cell viability in HCT116 (cancer) and HEK2931 IMR90 (non-cancerous) human cell lines following 24 Hrs treatment with 1 , 3 and 5 pM DRx-098D-R (N=3, MEAN ± SEM). HCT116 vs. HEK293 and IMR-90: **, P < 0.01 ; ***, P < 0.001 ; *“*, P < 0.0001 .

[0436] Figure 11: DRx-098D-R induced pro-apoptotic signalling

[0437] (A) Western immunoblotting of Cleaved PARP and Cleaved Caspase 3 pro-apoptotic protein markers in HCT116 human colorectal cancer cells following 24 Hrs treatment with vehicle (0.25% DMSO), [3 pM] DRx-097A-R, [3 pM] Idasanutlin or [3 pM] DRx-098D-R. Densitometry used to measure relative protein expression as a fold-difference vs. respective vehicle (PARP / Caspase normalised to GAPDH, N=1). (B) Expression of fluorescently labelled Annexin V (pro-apoptotic marker) binding was measured following treatment of HCT116 cells with Vehicle (0.25% DMSO), [3 pM] DRx-097A-R or [3 pM] DRx-098D-R for 6 or 24 Hrs [n=4, MEAN ± SEM], **, P < 0.01 vs. Vehicle and DRx-097A-R.

[0438] Figure 12: DRx-098D-R induced pro-apoptotic signalling

[0439] (A) MDM2, MDMX, p53 and p21 protein expression in HCT116 normalised to respective total protein following 24 Hrs treatment with vehicle (0.25% DMSO), [3 pM] DRx-097A-R, [3 pM] DRx-098D-R. Densitometry used to measure relative protein expression as a fold-difference vs. respective vehicle 008849002

[0440] 33

[0441] (MEAN ± SEM, N=2, n=4, ns: not significant, *: P < 0.05, ***: P < 0.001 , ****: P < 0.0001 ). (B) Representative western immunoblots and appropriate total protein control stain.

[0442] Figure 13: DRx-098D-R induced pro-apoptotic signalling

[0443] (A) MDM2, MDMX, p53 and p21 protein expression in HCT116 normalised to respective total protein following 24 Hrs treatment with vehicle (0.25% DMSO), [3 pM] DRx-097A-R, [3 pM] DRx-098D-R, followed by a 24 Hr period wash-out (‘recovery’). Densitometry used to measure relative protein expression as a fold-difference vs. respective vehicle (MEAN ± SEM, N=2, n=4, ns: not significant, **: P < 0.01 ). (B) Representative western immunoblots and appropriate total protein control stain.

[0444] Figure 14: DRx-098D-R is anti-proliferative in HCT116 p53 / _cell model

[0445] (A) End-point (CellTiter Gio) cell viability of human HCT116 p53 / _colorectal cancer cells were determined following 24 Hrs treatment (low serum - 2% FBS - conditions) with Vehicle (0.25% DMSO), [3 pM] negative control knock-out peptide DRx-097A-R, [3 pM] Idasanutlin, or [0.1 - 5 pM] dose response of DRx-098D-R. Relative cell viability normalised as a % difference of 100% vehicle control (N=3, MEAN ± SEM). Horizontal lines represent cell viability of vehicle treatment (100%), DRx-097A-R treatment, Idasanutlin treatment and growth IC50 (50% viability). (B) Direct comparison of relative cell viability following 24-hour treatment with Vehicle (0.25% DMSO) or equimolar concentrations [3 pM] of DRx- 097A-R, DRx-098D-R and Idasanutlin vs. HCT 116 p53- / - cells. (C) HCT116 p53- / - cells immunoassayed with DAPI (nuclei), MDM2 and MDMX (no. of cells: 79, 63X Objective), ns, not significant. * P < 0.05; One-way ANOVA.

[0446] Figure 15: DRx-098D-R inhibits human AML cell line viability

[0447] (A) End-point (Cell Titer Gio) cell viability of human TH P-1 (TP53 mutant) and MOLM-13 (TP53 Wild- Type) Acute Myeloid Leukaemia (AML) cell lines were determined following 72 Hrs treatment (low serum - 2% FBS - conditions) with Vehicle (0.25% DMSO) or [0.01 - 5 pM] dose response of DRx-098D-R. Relative cell viability normalised as a % difference of 100% vehicle control (N=3, MEAN ± SEM). Horizontal lines represent cell viability of vehicle treatment (100%) and growth IC50 (50% viability). (B) Respective Log[pM] IC50 of DRx-098D-R in MOLM-13 and THP-1 (N=3, MEAN ± SEM, ns: not significant).

[0448] Figure 16: DRx-098D-R induced pro-apoptotic signalling in human AML cell lines

[0449] Expression of fluorescently labelled Annexin V (pro-apoptotic marker) binding was measured following treatment of THP-1 (TP53 Mutant) Acute Myeloid Leukaemia (AML) cell line with Vehicle (0.25% DMSO), 008849002

[0450] 34

[0451] [3 or 5 pM] DRx-098D-R or [3 pM] Idasanutlin for 8 Hrs [n=4, MEAN ± SEM]. ***, P < 0.01 vs. Vehicle and

[0452] Idasanutlin.

[0453] Figure 17: DRx-098D-R cytotoxic activity vs. panel of human TP53 wild-type and mutant cancer cell lines

[0454] End-point (MTS) cell viability of human cancer cell lines (TP53 wild-type and mutant) following 24 Hrs treatment (low serum - 2% FBS - conditions) with Vehicle (0.25% DMSO), [0.1 - 5 pM] dose response of DRx-098D-R. Relative cell viability normalised as a % difference of respective 100% vehicle control (N=3- 4, MEAN ± SEM). Horizontal lines represent cell viability of vehicle treatment (100%) and growth IC50 (50% viability). Table indicates respective DRx-098D-R growth IC50 values [pM].

[0455] Figure 18: DRx-098D-R cytotoxic activity vs. panel of human TP53 wild-type and mutant cancer cell lines

[0456] (A) End-point (MTS) cell viability of human cancer cell lines (TP53 wild-type and mutant) following 24 Hrs treatment (low serum - 2% FBS - conditions) with Vehicle (0.25% DMSO), [3 pM] DRx-097A-R, [3 pM] DRx-098D-R or [3 pM] Idasanutlin. Relative cell viability normalised as a % difference of respective 100% vehicle control (N=3-4, MEAN ± SEM). Horizontal lines represent cell viability of vehicle treatment (100%). Ns, not significant; **, P < 0.01 ; ***, P < 0.001 ; P < 0.0001 vs. Vehicle control. (B) Corresponding comparison of cell viability following equimolar treatment with DRx-098D-R vs Idasanutlin in human cancer cell line panel (****, P < 0.0001).

[0457] Figure 19: Endogenous MDM2 / MDMX protein expression profile in human cancer cell line panel

[0458] (A) MDM2, MDMX and p53 protein expression normalised to respective total protein MEAN ± SEM, N3- 4). Black arrow indicative of low MDM2 / MDMX expressing PANC1 cell line. Densitometry used to measure relative / normalised protein expression, with respective statistical significance presented in corresponding tables (B). Ns, not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001 ; P < 0.0001.

[0459] Figure 20: Assessment of ‘next-generation’ MDM2 disruptor peptides vs. A549 cell viability via end-point MTS Assay

[0460] (A) 48 Hour, 6-point dose response curve [0.1 - 5 pM, low serum - 2% FBS - conditions], treatments of DRx-098D-R (positive control), DRx-990, DRx-991 , DRx-992, DRx-993, DRx-994. Vehicle (0.25% DMSO), DRx-097A-R [3 pM] (DRx-098D-R hotspot knockout negative control peptide) and DRx-992-C [3 pM] (DRx-990-992 negative control hotspot knockout peptide) controls also assessed. Experiment carried out at low (2% FBS) serum conditions. (B) Respective growth IC50 concentrations. (C) Direct comparison 008849002

[0461] 35 of equimolar concentrations of peptides DRx-097A-R, DRx-098D-R, DRx-990, DRx-991 , DRx-992, DRx- 992-C [3 pM], MEAN ± SEM, N=3. Ns, not significant; * P < 0.05; “ P < 0.01 ; One-way ANOVA.

[0462] Figure 21: RTCA xCELLigence growth analysis of next -generation MDM2 disruptor peptides vs. A549

[0463] (A) Real-time analysis of Vehicle (0.25% DMSO), DRx-098D-R [5 pM] (positive control), DRx-990-992 [5 pM], DRx-097A-R [5 pM] (DRx-098D-R negative control hotspot knockout peptide control), DRx-992-C [5 pM] (DRx-990-992 negative control hotspot knockout control peptide) vs. A549 human non-small cell lung cancer cell growth over a 48-hour treatment period (measurements every 15 minutes). Experiment carried out in high (10% FBS) serum conditions. Cell index was normalised to treatment time point and represented as a % difference of vehicle (100%). (B) Relative rate of growth of all individual treatments. N=3, MEAN ± SEM. Ns, not significant; ** P < 0.01 ; *** P < 0.001 ; **** P < 0.0001 ; One-way ANOVA.

[0464] Figure 22: DRx-098D-R, DRx-991 and DRx-992 downregulate endogenous MDM2:MDMX heterodimer complex formation

[0465] (A) Graph summarising proximity ligation signal (PLA signal) measured from the complex formation of full-length endogenous MDM2 and MDMX heterodimerisation in human A549 non-small cell lung cancer cells, following treatment with Vehicle (0.25% DMSO), DRx-097A-R [5 pM], DRx-098D-R [5 pM], DRx- 992-C [5 pM], DRx-992 [5 pM], DRx-992 [5 pM], Idasanutlin [5 pM] for 4 hours. (B) Representative images of A549 cells. Grey represents nuclei. White signal(s) represent formation of MDM2-MDM2 homodimers. Ns, not significant, **** P < 0.0001 ; One-way ANOVA. #cells per treatment arm = 23-44, 63X Objective.

[0466] Figure 23: Protein expression in A549 cells after DRx-992 treatment

[0467] (A) Representative western immunoblots showing MDM2, MDMX, p53, p21 and GAPDH endogenous protein expression in A549 cells following 0 Hr, 1 Hr, 2 Hrs, 4 Hrs, 24 Hrs and 24 Hrs (+24 Hr wash-out) treatment with [5 pM] DRx-992 (left) or DRx-992-C (negative control peptide) (right). (B) Densitometry used to measure relative protein expression as a fold-difference of respective 0 Hrs time point, and depicted as a heat map [RIGHT] (MEAN, N=3)

[0468] Figure 24: DRx-992 is significantly more anti-proliferative vs. a panel of human TP53 mutant Acute Myeloid Leukaemia (AML) cell lines than Idasanutlin

[0469] (A) End-point (Resazurin) cell viability of human TP53 mutant AML cell lines following 72 Hrs treatment (high FBS, complete medium) with Vehicle (DMSO), [0.1 - 10 pM] dose response of DRx-992 or (B) [0.001 - 20 pM] dose response of Idasanutlin. Data normalised as a % difference of respective 100% 008849002

[0470] 36 vehicle control (N>3, MEAN ± SEM). Horizontal lines represent cell viability of vehicle treatment (100%) and growth IC50 (50% viability). (C) Table of respective growth IC50 values [pM], with statistical significance compared between combined DRx-992 vs. Idasanutlin growth IC50 data.

[0471] Figure 25: DRx-992 has significantly higher anti-proliferative activity than Idasanutlin against a human MYCN amplified, TP53 mutant high-risk Neuroblastoma (HR-NB) cell line (SK-N-Be(2))

[0472] (A) End-point (MTS) cell viability of SK-N-Be(2) cells following 48 Hrs treatment (high FBS, complete medium) with Vehicle (DMSO), [0.1 - 10 pM] dose response of DRx-992 or (B) [0.1 - 10 pM] dose response of Idasanutlin. Data normalised as a % difference of respective 100% vehicle control (N=3, MEAN ± SEM). Horizontal lines represent cell viability of negative control peptide DRx-992-C [10 pM] and growth IC50 (50% viability). (B) RealTime-Glo Annexin V apoptosis assay carried out on SK-N-Be(2) cells following treatment with Vehicle (DMSO, 6 Hrs), DRx-992-C (3 pM, 6Hrs), DRx-992 (3 pM, 6 Hrs, 24 Hrs), Idasanutlin (3 pM, 6 Hrs). Data represented as a fold-difference of Vehicle [n=3, MEAN ± SEM]. ns, not significant, ***, P < 0.001 ; P < 0.0001 ; vs. Vehicle

[0473] Figure 26: Structure of DRx-992

[0474] Figure 27: DRx-992 is significantly more anti-proliferative vs. a panel of human TP53 mutant Neuroblastoma cell lines than Idasanutlin

[0475] (A) End-point (Cell-Titer Gio) cell viability of human TP53 mutant neuroblastoma cell lines following 72 Hrs treatment (high FBS, complete medium) with Vehicle (DMSO), [0.1 - 10 pM] dose response of DRx- 992 or (B) [0.001 - 20 pM] dose response of Idasanutlin. (C) Table summarising growth IC50 of both drugs against each cell line. Data normalised as a % difference of respective 100% vehicle control (N=3, MEAN ± SEM), *, P < 0.05.

[0476] Figure 28: DRx-992 downregulates c-MYC and MYCN expression.

[0477] (A) c-MYC (MYC) mRNA and (B) protein expression following 6 and 24 hr treatment with vehicle, DRx- 992-C [3 pM], or DRx-992 [3 pM], determined by RNA sequencing and western immunoblotting, respectively. (C) MYCN protein expression following 3 hr treatment with vehicle, DRx-992-C [5 pM], or DRx-992 [5 pM]. ns, not significant. **** P adj. < 0.0001 (DESeq2)

[0478] Figure 29: Global transcriptomic effect of DRx-992 vs. HL-60 AML cell line.

[0479] (A) Log2 fold changes (Log2_FC) of DRx-992-C and DRx-992 vs vehicle in HL-60 cells after 6 and 24 hrs. Significantly (P adj. < 0.05) upregulated (Log2_FC > 1) and downregulated (Log2_FC < -1) genes are highlighted. (B) Gene set enrichment analysis (GSEA) of significantly upregulated genes in HL-60 at 008849002

[0480] 37 both timepoints, highlighting key enriched pathways, their normalised enrichment score (NES), and their significance (-Iog10 P adj.)

[0481] Figure 30: DRx-992 promotes myeloid cell differentiation.

[0482] (A) CD11 b (ITGAM) mRNA expression following treatment with vehicle, DRx-992-C [3 pM], or DRx-992 [3 pM], determined by RNA sequencing. (B) Surface marker expression of CD11b and (C) CD14 in live (Annexin- / DAPI-) HL-60 cells following 24-72 hr peptide treatment, determined by flow cytometry. (D) mRNA expression (determined by RNA-seq) of primary azurophilic granule components myeloperoxidase (MPO), proteinase 3 (PRTN3), and cathepsin G (CTSG) in response to 6 and 24 hr peptide treatment. (E) KwikDiff morphology staining of HL-60 cells following 72 hr peptide treatment. (F) Heatmap of CD11 b+ % in HL-60 and MOLM-13 cells following 48 hr treatment with ATRA [10 / 100 or 100 / 1000 nM] and / or DRx- 992 [2, 3, 4 pM], determined by flow cytometry. RNA-seq data: ns, not significant; * P adj. < 0.05; **** P adj. < 0.0001 (DESeq2). Flow cytometry: ns, not significant; ** P < 0.01 ; **** P < 0.0001 (Two-way ANOVA).

[0483] Figure 31: MDM2-derived DRx-992 disruptor peptide is more anti-proliferative vs. TP53 mutant SK- N-Be(2) cells than MDMX-derived disruptor peptides.

[0484] (A)-(B) End-point (Cell-Titer Gio) cell viability of human TP53 mutant neuroblastoma cell lines following 72 Hrs treatment (high FBS, complete medium) with Vehicle (DMSO), [5 pM] DRx-992, [5 pM] DRx-992-C control, [5 pM] MDMX-3R, [5 pM] MDMX-9R, [5 pM] Idasanutlin. Data normalised as a % difference of respective 100% vehicle control (N=3, MEAN ± SEM).

[0485] Figure 32: Anti-proliferative impact additional modifications to DRx-992 vs. TP53 mutant SK-N- Be(2) cell line.

[0486] (A) Cyclised tetra-L-arginine - C12 short chain fatty acid incorporated cell-penetrating peptide, utilising a thioether conjugation approach. (B) Cyclised tetra-L-arginine - C12 short chain fatty acid incorporated cel I- penetrating peptide, utilising a Cys-Cys disulphide conjugation approach. (C) Table of modified peptide candidates with respective modification reference and relative growth IC50 vs, SK-N-Be(2) determined via end-point cell viability (Cell-Titer Gio) assay (120 Hrs treatment duration, 0.01 - 10 pM dose-range). (D) Summarised bar chart of relative growth IC50 of each peptide candidate vs. SK-N-Be(2).

[0487] Figure 33: 3277 is significantly more potent than DRx-992 vs. TP53 mutant Neuroblastoma SK-N- Be(2) cell line.

[0488] (A) End-point (Cell-Titer Gio) cell viability of human TP53 mutant neuroblastoma cell lines following 120 Hrs treatment (high FBS, complete medium) with Vehicle (DMSO), [0.1 - 10 pM] dose response of DRx- 008849002

[0489] 38

[0490] 992 or 3277. Data normalised as a % difference of respective 100% vehicle control (N=3, MEAN ± SEM), **, P < 0.01. (B) Chemdraw structure of 3277.

[0491] Detailed Description of the Invention

[0492] Aspects and embodiments of the present invention will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0493] Throughout the present description and claims the conventional three-letter and one-letter codes for naturally occurring amino acids are used, i.e.

[0494] A (Ala), G (Gly), L (Leu), I (He), V (Vai), F (Phe), W (Trp), S (Ser), T (Thr), Y (Tyr), N (Asn), Q (Gin), D (Asp), E (Glu), K (Lys), R (Arg), H (His), M (Met), C (Cys) and P (Pro).

[0495] By “naturally occurring” in this context is meant the 20 amino acids encoded by the standard genetic code, sometimes referred to as proteinogenic amino acids.

[0496] Less common or non-naturally occurring amino acids (i.e. amino acids other than the 20 encoded by the standard mammalian genetic code) may be referred to by their full name (e.g. sarcosine, ornithine, etc.) or by frequently employed three- or four-character codes. Examples include:

[0497] Norleucine (Nle; 2-aminohexanoic acid);

[0498] Orn (ornithine, i.e. 2,5-diaminopentanoic acid);

[0499] Dab (2,4-diaminobutanoic acid; e.g. (2S)-2,4-diaminobutanoic acid);

[0500] Dap (2,3-diaminopropanoic acid; e.g. (2S)-2,3-diaminopropanoic acid);

[0501] Aad (2-aminoadipic acid, e.g. (2S)-2-aminoadipic acid; also known as (2S)-2-aminohexanedioic acid or homo-glutamic acid); hLys (2-amino-7-amino-heptanoic acid, also known as homo-lysine, e.g. (2S)-2-amino-7-amino-heptanoic acid) hCys (homo-cysteine) chloroalanine (beta-chloroalanine; 3-chloroalanine)

[0502] R5 ((R)-2-Amino-2-methylhept-6-enoic acid)

[0503] S5 ( (S)-2-Amino-2-methylhept-6-enoic acid)

[0504] R8 ((R)-2-Amino-2-methyldec-9-enoic acid)

[0505] S8 ((S)-2-Amino-2-methyldec-9-enoic acid)

[0506] Aib (2-Aminoisobutyric acid) 008849002

[0507] 39

[0508] Pra (L-propargylg lycine)

[0509] Abu (aminobutyric acid) and its modified version AbuN3 ((S)-2-(amino)-4-azidobutanoic acid)

[0510] Nva (norvaline) and its modified version NvaN3 ((S)-2-(amino)-5-azidopentanoic acid)

[0511] N-methylated amino acids may also be employed. Sarcosine (Sar; N-methylglycine) is one example of an N-methylated amino acid, but N-methylated equivalents of any amino acid (other than proline) may be used. They may be designated [NMe-X] or [N-Me-X] where X is the single letter code, three letter code, or full name of the relevant residue.

[0512] When using the single letter code, lower case letters are used for amino acid residues of the D- configuration, and upper case letters for amino acid residues of the L-configuration. For non-chiral amino acid residues (e.g. glycine), either may be used. When the three letter code is used, the configuration D- or L- is typically indicated explicitly. If no configuration is shown, the L-configuration should be assumed.

[0513] When applied to a given amino acid sequence, the term "retro-inverso" is used to indicate an alternative form containing the same residues, in the opposite configuration (L or D), and in which the order of the residues from N- to C-terminus is reversed. The term is often used to refer to a reversed-sequence all-D version of a conventional peptide consisting of L-form residues. In the context of the present invention, a “retro-inverso” form of a peptide containing both L- and D-amino acids would have the reverse N- to C- orientation, with L-amino acids exchanged for D-amino acids and D-amino acids exchanged for L-amino- acids. Thus, for example, a retro-inverso version of the sequence [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle- Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3) would have the sequence Phe-Leu-[D-Thr]-[D-Leu]-[D-Val]- [D-lle]-Thr-[D-Gln]-[D-lle]-[D-Pro]-[D-Gln]-Arg.

[0514] The N-substituted glycines are closely related to proteinogenic or non-proteinogenic amino acids, but differ in that their side chains are linked to the backbone nitrogen atom rather than to the alpha-carbons (as in conventional amino acids). N-substituted glycine monomers may be designated by the prefix “N-” applied to the designation of the amino acid with the corresponding side chain. Thus, by way of illustration, N-Arg refers to N-substituted glycine with an arginine side chain ((3-guanidinopropylamino)- acetic acid), N-GIn refers to N-substituted glycine with a glutamine sidechain ((2-carbamoyl-ethylamino)- acetic acid), and N-Tyr refers to N-substituted glycine with a tyrosine sidechain (N-(4- hydroxyphenyl)glycine). The meaning of other abbreviations will be apparent from the context.

[0515] The N-substituted glycines are not chiral and so do not typically have L and D enantiomers.

[0516] Illustrative formulae for N-Tyr, N-Arg and N-GIn residues (as part of a longer peptide or peptoid chain) are provided below. 008849002

[0517] 40

[0518] The term “peptoid” is used in this specification to designate a peptidomimetic sequence or molecule composed entirely of N-substituted glycine monomers. However, it will be understood that N-substituted glycine units may also be used in combination with conventional amino acids. Molecules containing both conventional amino acids and N-substituted glycine units are considered simply as peptides for the purposes of this specification. It will be understood that the moieties P and X may independently be peptide or peptoid moieties, and that the MDM2 inhibitor may therefore comprise a peptide linked to a peptoid.

[0519] Without wishing to be bound by theory, it is believed that identity of the amino acid side chains at each position may be more important to the peptide’s function than whether they are part of an L amino acid residue, a D amino acid residue, an N-methylated amino acid residue (of L or D configuration), or an N- substituted glycine residue. Thus, for any given side chain, these different forms may be regarded as equivalents of one another, rather than as one being a substitution for another.

[0520] In some embodiments, the disruptor component P comprises only L and / or D amino acids. 008849002

[0521] 41

[0522] The terminal functional groups at the amino and carboxyl termini of the peptide chain of P may be free amino and carboxyl groups respectively. Alternatively, either or both may be linked to a heterologous moiety, such as a half-life extending moiety or a cell transit moiety. Alternatively, either or both may be derivatised to increase stability. Thus the N-terminal amino group may be represented by -NH-Y1 , where Y1 may be hydrogen (H), acetyl (Ac) or a heterologous moiety such as a half-life extending moiety or a cell transit moiety. The C-terminal carboxyl group may be represented by -C(O)-Y2, where Y2 may be OH (forming a terminal carboxylic acid group), NH2 (forming a terminal amide), or a heterologous moiety such as a half-life extending moiety or a cell transit moiety. It may be convenient simply to indicate the Y1 and Y2 groups. Thus "Ac” at the N-terminus may be taken to indicate an acetylated N-terminal amino group (-NH-Ac), while -NH2 at the C-terminus may be taken to indicate an amidated C-terminal carboxyl group (-C(O)-NH2).

[0523] MDM2 inhibitor

[0524] The MDM2 (mouse double minute 2 homolog) protein, sometimes referred to as HDM2, is encoded in humans by the mdm2 gene. The full length transcript encodes a protein of 491 amino acids containing an N-terminal p53 interaction domain, a central acidic domain containing phosphorylation sites and nuclear import and export signals, a zinc finger domain, and a C-terminal RING domain which contains two coordinated zinc ions and possesses E3 ubiquitin ligase activity.

[0525] MDM2 is active either as a homodimer (MDM2:MDM2) or as a heterodimer with MDMX (MDM2:MDMX). Dimerisation is mediated via the RING domain, and is necessary for E3 ubiquitin ligase activity. (MDMX is sometimes also referred to as MDM4, or alternatively as either HDMX or HDM4.)

[0526] MDM2 acts as a negative regulator of the p53 tumour suppressor via a number of mechanisms. It binds to the N-terminal trans-activation domain of p53 and inhibits the transcription-promoting activity of p53 via its N-terminal p53 interaction domain. It is also capable of ubiquitinating p53 and other targets via the RING domain of MDM2, thus targeting them for degradation via the proteosome. MDMX does not have intrinsic E3 ligase activity.

[0527] A number of current clinical candidate therapeutics (e.g., Idasanutlin, AMG-232, ALRN-6924) target MDM2 and / or MDMX in a p53 dependent manner (6-7). Though this approach has proven successful in TP53 wild-type cancer, it does not translate to cancers harbouring a loss-of-function TP53 mutation (7).

[0528] A number of peptides derived from the RING domain of MDMX (MDM4) have been identified as potential inhibitors of MDM2:MDMX heterodimerisation (17, 18). However, the authors of these papers did not investigate the capacity of these peptides to inhibit MDM2:MDM2 homodimerisation, which remains 008849002

[0529] 42 functionally significant, or to affect p53-independent pathways of tumorigenesis. Indeed, while MDM2 and MDMX affect tumorigenesis through a number of p53-independent signalling pathways, this remains an area of research in its infancy (3-7).

[0530] MDM2 dimerisation (whether homodimerisation or heterodimerisation) has been implicated in a range of cancers of different lineages, including many solid tumours and blood cancers. Consistent with this, the Examples below show anti-proliferative activity of the peptides of the invention against human cancer cell lines derived from (at least) neuroblastoma, acute myeloid leukaemia, lung cancer, colorectal cancer, osteosarcoma, melanoma and pancreatic cancer. All of these therefore represent candidates for treatment, as do myeloprolfierative neoplasms (including polycythemia vera and myelofibrosis) which are often precursors to acute myeloid leukaemia. Anti-proliferative activity correlates with the relative expression levels of MDM2 and MDMX and is independent of TP53 mutational status. Thus, any cancer showing significant levels of MDM2 and / or MDMX expression are likely to be viable targets for treatment using the inhibitors described herein. Cancers with Myc amplification or overexpression are also likely to be viable candidates for treatment, since Myc expression often correlates well with MDM2 expression. Thus, cancers which are driven by c-MYC / MYCN signaling may be suitable therapeutic targets. Further candidate cancers may comprise neuroblastoma, leukemia (e.g., acute myeloid leukaemia (AML) including acute promyelocytic leukaemia (APL)), colorectal cancer (e.g., poorly differentiated colorectal cancer), osteosarcoma, liver cancer (e.g., hepatocellular carcinoma), prostate cancer (e.g., neuroendocrine prostate cancer), rhabdomyosarcoma, and glioma (e.g., paediatric high-grade glioma).

[0531] MDM2 has also been shown to have a disease-promoting role in various other conditions, such as: inflammatory disease, including (but not limited to) autoimmune diseases, e.g. rheumatoid arthritis, systemic lupus erythaematosus (SLE), pancreatitis and gastritis; dementia and neurodegenerative diseases, e.g. fragile X syndrome, Parkinson’s disease and Alzheimer’s disease; nephropathy, e.g. autosomal dominant polycystic kidney disease, renal fibrosis, diabetic nephropathy and crescentic glomerulonephritis; heart and cardiovascular disease, e.g. heart failure, myocardial infarction and atherosclerosis.

[0532] In addition to the effect on p53 described herein, and without wishing to be bound by theory, it is anticipated that the MDM2 inhibitors as described herein may function to transcriptionally reprogramme and revert malignant cancer phenotypes to more differentiated states (i.e., differentiation-inducing), rendering the cancer less aggressive. It is also anticipated that this effect may render the tumour more amenable to conventional therapeutic approaches. Thus, the MDM2 inhibitors described herein may be used as a monotherapy or as a combination therapy. 008849002

[0533] 43

[0534] In some embodiments, cancers for treatment include neuroblastoma, a myeloproliferative neoplasm (e.g. polycythemia vera or myelofibrosis), leukaemia (e.g. acute myeloid leukaemia (AML) as well as subtypes thereof such as acute promyelocytic leukaemia (APL)), lung cancer, colorectal cancer (e.g., poorly differentiated colorectal cancer), osteosarcoma, melanoma, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), prostate cancer (e.g., neuroendocrine prostate cancer), rhabdomyosarcoma, and glioma (e.g., paediatric high-grade glioma). In some embodiments, the cancer is acute myeloid leukaemia. In a further embodiment, the cancer is acute promyelocytic leukaemia (APL).

[0535] In some aspects of the invention, the MDM2 inhibitors described herein may also be used in the treatment or prophylaxis of cancer in a subject alongside or in combination with one or more additional therapeutic agents. The therapeutic agents may be chemotherapeutic agents. The therapeutic agents may be chemotherapeutic agents or one or more additional differentiation-inducing agents. In some embodiments, the MDM2 inhibitors of the present invention may also be used in the treatment or prophylaxis of cancer in a subject in combination with one or more (additional) differentiation-inducing agents.

[0536] Differentiation-inducing agents are agents that capable of promoting cell differentiation. Examples, which may be used within the context of the invention include retinoic acid and retinoic acid derivatives, arsenic trioxide (ATO), cAMP, sodium butyrate and cytokines. The retinoic acid derivates may be selected from all-trans retinoic acid (ATRA), 13 cis-retinoic acid (13-cis RA), and 9-cis retinoic acid. The cytokines may be selected from the group consisting of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3), and transforming growth factor-beta (TGF- ). Other examples of differentiationinducing agents include dimethyl sulfoxide, active form vitamin D(3), peroxisome proliferator-activated receptorgamma, 12-Myristate 13-acetate (PMA), hexamethylene-bis-acetamide, butyric acid, and vesnarinone. In some embodiments, the differentiation-inducing agent is selected from the group consisting of retinoic acid and retinoic acid derivatives, arsenic trioxide (ATO), cAMP, sodium butyrate, cytokines, dimethyl sulfoxide, active form vitamin D(3), peroxisome proliferator-activated receptorgamma, 12-Myristate 13-acetate (PMA), hexamethylene-bis-acetamide, butyric acid, and vesnarinone.

[0537] Without wishing to be bound by theory, the combined use of the MDM2 inhibitor described herein and the differentiation-inducing agent is considered to result in a synergistic therapeutic effect.

[0538] In some aspects and embodiments, the MDM2 inhibitor described herein and a differentiation-inducing agent may be provided as a combination therapy. In some embodiments, the MDM2 inhibitor and differentiation-inducing agent may be administered simultaneously or sequentially. Simultaneous administration refers to administration of the two or more agents together, for example as a pharmaceutical composition containing both agents (i.e. , as a combined preparation), or immediately after one another, and optionally via the same route of administration, e.g., to the same artery, vein, or other blood vessel. Sequential administration refers to administration of one of the agents followed after a given time interval by separate administration of another agent. In other words, the MDM2 inhibitor and the differentiation-inducing agent are administered separately. It is not required that the agents are 008849002

[0539] 44 administered by the same route, although this is the case in some embodiments. The time interval may be any suitable time interval.

[0540] The present disclosure also provides the MDM2 inhibitor as described herein for use in a method of treating cancer, wherein the method further comprises administering a differentiation-inducing agent. Also provided is the use of the MDM2 inhibitor described herein in the manufacture of a medicament for use in a method of treating cancer, wherein the MDM2 inhibitor is for administration with a differentiationinducing agent. The disclosure also provides a method of treating cancer, the method comprising a therapeutically- or prophylactically-effective amount of the MDM2 inhibitor described herein to subject in need of treatment, wherein the method further comprises subjecting the subject to a differentiationinducing agent.

[0541] Also provided is a composition comprising an MDM2 inhibitor as described herein and a differentiationinducing agent for use in a method of treatment or prophylaxis of cancer. The invention further provides a method of treating cancer, comprising administering an effective amount of a composition comprising a MDM2 inhibitor as described herein and a differentiation-inducing agent to an individual in need thereof. The invention further provides the use of a composition comprising a MDM2 inhibitor as described herein and a differentiation-inducing agent in the manufacture of a medicament for the treatment of cancer.

[0542] Pharmaceutical Compositions

[0543] The MDM2 inhibitors described in this specification can be formulated in pharmaceutical compositions. These compositions may comprise, in addition to one of the above substances, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material may depend on the route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes or topical application.

[0544] Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may include a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.

[0545] For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, 008849002

[0546] 45

[0547] Lactated Ringer's Injection. Preservatives, stabilisers, buffers, antioxidants and / or other additives may be included, as required.

[0548] Administration is preferably in a “prophylactically effective amount” or a "therapeutically effective amount" (as the case may be, although prophylaxis may be considered therapy), this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Suitable carriers, adjuvants, excipients, etc. can be found in standard pharmaceutical texts, for example Remington’s Pharmaceutical Sciences, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.

[0549] When the MDM2 inhibitor does not comprise a membrane transit moiety, it may be provided in non- covalent association with a membrane transit agent, e.g. in a mixture with a membrane transit agent, or encapsulated within a membrane transit agent. For example, the agent may be a liposome-forming agent, and the MDM2 inhibitor may be encapsulated within a liposome or liposomes.

[0550] Salts and Solvates

[0551] The agents described herein may be provided in the form of a suitable salt, such as pharmaceutically acceptable salts. Suitable salts include those formed with organic or inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed with hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycollic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, p- toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, and isethionic acids. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutical acceptable salts. Pharmaceutically acceptable salts with bases include ammonium salts, alkali metal salts, for example potassium and sodium salts, alkaline earth metal salts, for example calcium and magnesium salts, and salts with organic bases, for example dicyclohexylamine and N-methyl-D-glucomine.

[0552] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. Such complexes are known as "solvates". For example, a complex with water is known as a "hydrate". The present invention provides solvates of compounds of the invention.

[0553] Peptide Synthesis 008849002

[0554] 46

[0555] The MDM2 inhibitors of the invention may be made by any suitable technique for making peptides, including but not limited to conventional methodology, for example, synthesis from individual amino acids, especially step-wise synthesis using an automatic peptide synthesizer; modification of native peptides; or recombinant manufacturing techniques.

[0556] In general, it will be preferred to synthesise the inhibitors by means of solid-phase or liquid-phase peptide synthesis methodology. In this context, reference may be made, for example, to Fields, G.B. et al., 2002, ‘‘Principles and practice of solid-phase peptide synthesis”. In: Synthetic Peptides (2nd Edition). The skilled person will be well aware of suitable methodologies.

[0557] The individual peptide components (P, and Z where appropriate) may alternatively be produced by recombinant methods, e.g. by expressing a precursor peptide sequence from a nucleic acid construct that encodes the precursor peptide, recovering the expression product, and modifying the precursor peptide to yield a MDM2 inhibitor of the invention. Expression may be performed in a host cell or in a cell-free expression system. When producing the precursor peptide from cells, it may be convenient that the expression product is secreted into the culture medium.

[0558] The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.

[0559] While the invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the invention.

[0560] For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

[0561] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0562] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise” and “include”, and variations such as “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 008849002

[0563] 47

[0564] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means for example + / - 10%.

[0565] 008849002

[0566] 48

[0567] The following numbered clauses represent embodiments and aspects of the invention:

[0568] 1. A MDM2 inhibitor comprising a disruptor component P which is capable of inhibiting MDM2:MDM2 homodimerisation and / or MDM2:MDMX heterodimerisation, wherein said disruptor component P is a peptide of at least 12 and no more than 20 residues in length, comprising

[0569] (i) a core sequence

[0570] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1 ) or an all-D or retro-inverso form thereof;

[0571] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2) or a retro-inverso form thereof;

[0572] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3) or a retro-inverso- form thereof;

[0573] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0574] (iii) a peptoid or N-methyl version of (i) or (ii).

[0575] 2. A MDM2 inhibitor according to clause 1 , wherein P comprises:

[0576] Arg or D-Arg at position 1 , or an N-methyl or N-substituted glycine analogue thereof;

[0577] Tyr, Trp, Phe, Leu, He or Vai at position 11 , or a D-form, N-methyl or N-substituted glycine analogue thereof; and / or

[0578] Phe, Trp, Tyr, Leu, He or Vai at position 12, or a D-form, N-methyl or N-substituted glycine analogue thereof. 008849002

[0579] 49

[0580] 3. A MDM2 inhibitor according to clause 1 or clause 2, wherein P comprises all three of:

[0581] Arg or D-Arg at position 1 , or an N-methyl or N-substituted glycine analogue thereof;

[0582] Tyr, Trp, Phe, Leu, He or Vai at position 11 , or a D-form, N-methyl or N-substituted glycine analogue thereof; and

[0583] Phe, Trp, Tyr, Leu, He or Vai at position 12, or a D-form, N-methyl or N-substituted glycine analogue thereof.

[0584] 4. A MDM2 inhibitor according to any one of the preceding clauses, wherein the residues at positions 4 and 7 or at positions 4 and 8 are a pair of residues <D and whose side chains participate in a covalent bond.

[0585] 5. A MDM2 inhibitor according to clause 4, wherein the covalent bond is a disulfide bond, a thioether bond, a lactam bond or an all hydrocarbon bond.

[0586] 6. A MDM2 inhibitor according to any one of the preceding clauses, further comprising one or more heterologous moieties.

[0587] 7. A MDM2 inhibitor according to clause 6, wherein the heterologous moiety is linked to a side chain of P at a residue or to a N-terminal or C-terminal functional group.

[0588] 8. A MDM2 inhibitor according to clause 7, wherein the residue is at position 0 or position 9 of P.

[0589] 9. A MDM2 inhibitor according to clause 7 or clause 8, wherein the residue is Cys, hCys, or a D- form of either.

[0590] 10. A MDM2 inhibitor according to any one of clauses 6 to 9, wherein the heterologous moiety is a membrane transit moiety.

[0591] 11. A MDM2 inhibitor according to clause 10, wherein the membrane transit moiety comprises a fatty acid, lipid or steroid. 008849002

[0592] 50

[0593] 12. A MDM2 inhibitor according to clause 10, wherein the membrane transit moiety is a cell penetrating peptide.

[0594] 13. A MDM2 inhibitor according to clause 12, wherein the cell penetrating peptide forms a fusion protein with P.

[0595] 14. AMDM2 inhibitor according to clause 13, wherein the cell penetrating peptide is located N- terminal of the core sequence and is optionally spaced from the N-terminus of the core sequence by a linker peptide.

[0596] 15. An MDM2 inhibitor according to any one of clauses 12 to 14, wherein the cell penetrating peptide is poly-arginine, poly-D-arginine, GRKKRRQRRR, Grkkrrqrrr, cyclo[GRKKRRQRRR] or cyclo[Grkkrrqrrr].

[0597] 16. AMDM2 inhibitor according to clause 15, wherein the cell penetrating peptide is_Arg4-io or [D- Arg]4-io, e.g. Args, Args, [D-Arg]s or [D-Arg]s.

[0598] 17. A MDM2 inhibitor according to any one of the preceding clauses, wherein the core sequence has the formula:

[0599] X1 -X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12 wherein

[0600] X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[0601] X2 is selected from Gin, Phe, Tyr, Leu, He, Gly, Met, Cys, His, Thr, Pro, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[0602] X3 is selected from Pro, Gly, Cys, His, Thr, Gin, Asn and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or a residue

[0603] X4 is selected from He, Trp, Phe, Tyr, Leu, Vai, Gly, Met, Cys, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof, or is a residue <D or

[0604] X5 is selected from Gin, Trp, Phe, Leu, lie, Vai, Met, His, Thr, Pro, Ser and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof; 008849002

[0605] 51

[0606] X6 is selected from Met, Tyr, Leu, He, Vai, Gly, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N- substituted glycine analogue thereof;

[0607] X7 is selected from He, Phe, Tyr, Leu, Vai, Met, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue 4*;

[0608] X8 is selected from Vai, Trp, Phe, Tyr, Leu, lie, Gly, Met, Cys, His, Thr, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue *;

[0609] X9 is selected from Leu, Trp, Phe, Tyr, lie, Vai, Gly, Met, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0610] X10 is selected from Thr, Phe, Leu, lie, Vai, Gly, Met, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0611] X11 is selected from Tyr, Trp, Phe, Leu, lie, Vai, Gly, Met, Cys, His, Thr, Pro, Gin, Asn, Ser, Glu, Arg and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0612] X12 is selected from Phe, Trp, Tyr, Leu, lie, Vai, Gly, Met, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue 4^ and vice versa, a maximum of one residue 41is present, and, when present, the side chains of residues <D and 4* form a covalent bond; where the side chain of any residue £ forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[0613] (i)

[0614] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;

[0615] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0616] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[0617] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0618] (iii) a peptoid, N-methyl or retro-inverso version of (i) or (ii). 008849002

[0619] 52

[0620] 18. A MDM2 inhibitor according to clause 17, wherein:

[0621] XI is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[0622] X2 is selected from Gin, Phe, Tyr, Leu, He, Gly, Met, Cys, His, Thr, Pro, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[0623] X3 is selected from Pro, Gly, Cys, His, Thr, Gin, Asn and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0624] X4 is selected from He, Trp, Phe, Tyr, Leu, Vai, Gly, Met, Cys, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof, or is a residue <D or ;

[0625] X5 is selected from Gin, Trp, Phe, Leu, lie, Vai, Met, His, Thr, Pro, Ser and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0626] X6 is selected from Met, Tyr, Leu, lie, Vai, Gly, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N- substituted glycine analogue thereof;

[0627] X7 is selected from lie, Phe, Tyr, Leu, Vai, Met, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ^P;

[0628] X8 is selected from Vai, Trp, Phe, Tyr, Leu, lie, Gly, Met, Cys, His, Thr, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue 4^;

[0629] X9 is selected from Leu, Trp, Phe, Tyr, lie, Vai, Gly, Met, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[0630] X10 is selected from Thr, Phe, Leu, lie, Vai, Gly, Met, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0631] XI I is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;

[0632] X12 is selected from Phe, Trp, Tyr, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue * and vice versa, a maximum of one residue ^P is present, and, when present, the side chains of residues <D and 'P form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is: 008849002

[0633] 53

[0634] (i)

[0635] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;

[0636] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0637] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[0638] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0639] (iii) a peptoid, N-methyl or retro-inverso version of (i) or (ii).

[0640] 19. A MDM2 inhibitor according to clause 17 or clause 18, wherein:

[0641] X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[0642] X2 is selected from Gin, Gly, His, Thr, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0643] X3 is selected from Pro, Gly and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[0644] X4 is selected from He, Trp, Tyr, Leu, Vai, Gly, His, Thr, Gin and Ser, or a D-form, N-methyl, or N- substituted glycine analogue thereof, or is a residue

[0645] X5 is selected from Gin, His, Thr and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0646] X6 is selected from Met, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0647] X7 is selected from He, Phe, Tyr, Leu, Vai, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue1;

[0648] X8 is selected from Vai, Phe, Tyr, Leu, lie, Thr, Asn, Ser, Asp and Glu, or a D-form, N-methyl, or N- substituted glycine analogue thereof, or is a residue

[0649] X9 is selected from Leu, Phe, Tyr, lie, Vai, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue (; 008849002

[0650] 54

[0651] X10 is selected from Thr, Gly, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0652] X11 is selected from Tyr, Trp, Phe, Leu, He and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;

[0653] X12 is selected from Phe, Trp, Tyr, Leu, He and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue * and vice versa, a maximum of one residue MJ is present, and, when present, the side chains of residues 0 and MJ form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[0654] (i)

[0655] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1 ) or an all-D form thereof;

[0656] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0657] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[0658] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0659] (iii) a peptoid, N-methyl version or retro-inverso form of (i) or (ii).

[0660] 20. A MDM2 inhibitor according to any one of clauses 17 to 19, wherein:

[0661] X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[0662] X2 is selected from Gin, Gly, His, Thr, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue 008849002

[0663] 55

[0664] X3 is selected from Pro, Gly and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[0665] X4 is selected from He, Gly, His, Thr, Gin and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue or

[0666] X5 is selected from Gin, His, Thr and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0667] X6 is selected from Met, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0668] X7 is selected from He, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue HJ;

[0669] X8 is selected from Vai, Thr, Asn, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue1;

[0670] X9 is selected from Leu, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0671] X10 is selected from Thr, Gly, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0672] X11 is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;

[0673] X12 is selected from Phe, Trp, Tyr, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue and vice versa, a maximum of one residue1is present, and, when present, the side chains of residues 4) and form a covalent bond; where the side chain of any residue £ forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[0674] (i)

[0675] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;

[0676] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2); 008849002

[0677] 56

[0678] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[0679] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0680] (iii) a peptoid, N-methyl version or retro-inverso form of (i) or (ii).

[0681] 21. A MDM2 inhibitor according to any one of clauses 17 to 20, wherein the core sequence has the formula:

[0682] X1-Gln-Pro-X4-Gln-X6-X7-X8-X9-Thr-X11-X12 where

[0683] XI is selected from Arg and D-Arg

[0684] X4 is He, or is a residue

[0685] X6 is selected from Met and Thr, or a D-form thereof;

[0686] X7 is He, or is a residue MJ;

[0687] X8 is Vai, or is a residue MJ;

[0688] X9 is Leu, or is a residue ;

[0689] XI I is selected from Tyr and Leu, or a D-form thereof;

[0690] X12 is selected from Phe and D-Phe

[0691] 22. A MDM2 inhibitor according to any one of clauses 17 to 21 , wherein the disruptor component P comprises additional sequence N- or C-terminal of the core sequence.

[0692] 23. A MDM2 inhibitor according to clause 22, wherein P comprises a residue N-terminal of the core sequence, e.g. at position X0.

[0693] 24. A MDM2 inhibitor according to clause 23, wherein the residue is Cys, hCys, or a D-form of either. 008849002

[0694] 57

[0695] 25. A MDM2 inhibitor according to any one of clauses 17 to 24, wherein P comprises a maximum of one residue

[0696] 26. A MDM2 inhibitor according to any one of the preceding clauses, wherein the core sequence comprises a sequence selected from:

[0697] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1 );

[0698] Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0699] [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; and

[0700] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe; or a peptoid, N-methyl or retro-inverso version thereof.

[0701] 27. A MDM2 inhibitor according to any one of clauses 1 to 25, wherein the core sequence comprises a sequence selected from:

[0702] Arg-GIn-Pro-cD-GIn-Met-lle-^P-Leu-Thr-Leu-Phe;

[0703] Arg-GIn-Pro-cD-GIn-Met-lle-^-Leu-Thr-tD-LeuHD-Phe];

[0704] [D-Arg]-Gln-Pro-<D-Gln-[D-Thr]-lle-^-Leu-Thr-[D-Leu]-[D-Phe];

[0705] Arg-GIn-Pro-cD-GIn-Met-lle-^P-Leu-Thr-Tyr-Phe;

[0706] Arg-GIn-Pro-cD-GIn-Met-'+’-Val-Leu-Thr-Leu-Phe;

[0707] Arg-Gln-Pro-<D-Gln-Met-iP-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0708] [D-Arg]-Gln-Pro-<D-Gln-[D-Thr]-iP-Val-Leu-Thr-[D-Leu]-[D-Phe]; and

[0709] Arg-GIn-Pro-dJ-GIn-Met-'+’-Val-Leu-Thr-Tyr-Phe; where the side chains of residues and form a covalent bond; or a peptoid, N-methyl or retro-inverso version thereof.

[0710] 28. A MDM2 inhibitor according to any one of clauses 1 to 25, wherein the disruptor component P comprises a sequence selected from:

[0711] ^-Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe;

[0712] £-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0713] <-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0714] ^-Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe; 008849002

[0715] 58

[0716] Arg-GIn-Pro-lle-GIn-Met-lle-Val-^-Thr-Leu-Phe;

[0717] Arg-Gln-Pro-lle-Gln-Met-lle-Val-<-Thr-[D-Leu]-[D-Phe];

[0718] [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-<-Thr-[D-Leu]-[D-Phe]; and

[0719] Arg-GIn-Pro-lle-GIn-Met-lle-Val-^-Thr-Tyr-Phe; where the side chain of the residue i, forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof.

[0720] 29. A MDM2 inhibitor according to any one of clauses 1 to 25, wherein the disruptor component P comprises a sequence selected from:

[0721] (-Arg-GIn-Pro-cb-GIn-Met-lle-^P-Leu-Thr-Leu-Phe;

[0722] <-Arg-Gln-Pro-0-Gln-Met-lle-^-Leu-Thr-[D-Leu]-[D-Phe];

[0723] <-[D-Arg]-Gln-Pro-ct>-Gln-[D-Thr]-lle-^-Leu-Thr-[D-Leu]-[D-Phe];

[0724] (-Arg-GIn-Pro-cb-GIn-Met-lle-^P-Leu-Thr-Tyr-Phe;

[0725] (-Arg-GIn-Pro-cb-GIn-Met-^P-Val-Leu-Thr-Leu-Phe;

[0726] <-Arg-Gln-Pro-<D-Gln-Met-iP-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0727] <-[D-Arg]-Gln-Pro-cb-Gln-[D-Thr]-^-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0728] (-Arg-GIn-Pro-cb-GIn-Met-^P-Val-Leu-Thr-Tyr-Phe;

[0729] Arg-Gln-Pro-<t>-Gln-Met-lle-'4J-£-Thr-Leu-Phe;

[0730] Arg-Gln-Pro-<D-Gln-Met-lle-^-<-Thr-[D-Leu]-[D-Phe];

[0731] [D-Arg]-Gln-Pro-<D-Gln-[D-Thr]-lle-^-<-Thr-[D-Leu]-[D-Phe];

[0732] Arg-Gln-Pro-<D-Gln-Met-lle-'4J-(-Thr-Tyr-Phe;

[0733] Arg-GIn-Pro-O-GIn-Met-'+’-Val-^-Thr-Leu-Phe;

[0734] Arg-Gln-Pro-(U-Gln-Met-4’-Val-<-Thr-[D-Leu]-[D-Phe];

[0735] [D-Arg]-Gln-Pro-<b-Gln-[D-Thr]-MJ-Val <-Thr-[D-Leu]-[D-Phe]; and

[0736] Arg-GIn-Pro-O-GIn-Met-'+’-Val-^-Thr-Tyr-Phe; 008849002

[0737] 59 where the side chains of residues and1form a covalent bond; and where the side chain of the residue forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof.

[0738] 30. A MDM2 inhibitor according to any one of the preceding clauses, having the formula

[0739] Z-L-P where

[0740] Z is a cell penetrating peptide;

[0741] P is the disruptor component; and

[0742] L is a linker peptide sequence (e.g. of 1-10 amino acids, e.g. of 1-5 amino acids), or represents a bond between Z and P; or a peptoid, N-methyl or retro-inverso version thereof.

[0743] 31 . A MDM2 inhibitor according to clause 30, having the formula

[0744] Y1 -Z-L-P- Y2 where

[0745] Y1 is H, Ac cr a heterologous moiety (e.g. H or Ac);

[0746] Z is a cell penetrating peptide;

[0747] P is the disruptor component;

[0748] L is a linker peptide sequence (e.g. of 1-10 amino acids, e.g. of 1-5 amino acids), or represents a bond between Z and P; and

[0749] Y2 is OH, NH2 or a heterologous moiety (e.g. OH or NH2).

[0750] 32. A MDM2 inhibitor according to any one of clauses 1 to 29, having the formula

[0751] Y1-P-Y2 where

[0752] Y1 is H, Ac or a heterologous moiety;

[0753] P is the disruptor component; and

[0754] Y2 is OH, NH2 or a heterologous moiety (e.g. OH or NH2). 008849002

[0755] 60

[0756] 33. A MDM2 inhibitor according to any one of the preceding clauses, comprising the sequence:

[0757] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe;

[0758] (Stearoyl)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe;

[0759] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe;

[0760] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Tyr]-[D-Phe];

[0761] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Leu-Phe;

[0762] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0763] [D-Arg]8-Cys-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0764] Cys(-Ac-[D-Arg]9-NH2)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; or

[0765] [D-Cys](-Ac-[D-Arg]9-NH2)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; or a peptoid, N-methyl or retro-inverso version thereof.

[0766] 34. A MDM2 inhibitor selected from:

[0767] Ac-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe-NH2;

[0768] (Stearoyl)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe-NH2 (DRx-97-S);

[0769] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe -NH2 (DRx-97-R);

[0770] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Tyr]-[D-Phe]-NH2(DRx-97D-R);

[0771] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Leu-Phe-NH2 (DRx-98R);

[0772] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-98D-R);

[0773] Ac-[D-Arg]8-Cys-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-990);

[0774] Ac-Cys(-Ac-[D-Arg]9-NH2)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2 (DRx-991 ); and

[0775] Ac-[D-Cys](-Ac-[D-Arg]9-NH2)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2 (DRx- 992); or a peptoid, N-methyl or retro-inverso version thereof.

[0776] 35. A MDM2 inhibitor according to any one of the preceding clauses for use in a method of medical treatment. 008849002

[0777] 61

[0778] 36. A MDM2 inhibitor according to any one of clauses 1 to 34 for use in the treatment of cancer, inflammatory disease, dementia or a neurodegenerative disease, nephropathy, or heart or cardiovascular disease.

[0779] 37. A MDM2 inhibitor for use according to clause 36, wherein the cancer is neuroblastoma, a myeloproliferative neoplasm (e.g. polycythemia vera or myelofibrosis), leukaemia (e.g. acute myeloid leukaemia,) lung cancer, colorectal cancer, osteosarcoma, melanoma or pancreatic cancer.

[0780] 38. A MDM2 inhibitor for use according to clause 36, wherein the inflammatory disease is an autoimmune disease, e.g. rheumatoid arthritis, systemic lupus erythaematosus (SLE), pancreatitis or gastritis.

[0781] 39. A MDM2 inhibitor for use according to clause 36, wherein the dementia or neurodegenerative disease is, or is associated with, for example, fragile X syndrome, Parkinson’s disease or Alzheimer’s disease.

[0782] 40. A MDM2 inhibitor for use according to clause 36, wherein the nephropathy is autosomal dominant polycystic kidney disease, renal fibrosis or diabetic nephropathy.

[0783] 41. A MDM2 inhibitor for use according to clause 36, wherein the cardiovascular disease is myocardial infarction or atherosclerosis.

[0784] 42. A pharmaceutical composition comprising a MDM2 inhibitor according to any one of clauses 1 to 34, optionally in combination with a pharmaceutically acceptable excipient.

[0785] 008849002

[0786] 62

[0787] The following numbered embodiments represent embodiments and aspects of the invention:

[0788] 1. A MDM2 inhibitor comprising a disruptor component P which is capable of inhibiting MDM2:MDM2 homodimerisation and / or MDM2:MDMX heterodimerisation, wherein said disruptor component P is a peptide of at least 12 and no more than 20 residues in length, comprising

[0789] (i) a core sequence

[0790] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1 ) or an all-D or retro-inverso form thereof;

[0791] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2) or a retro-inverso form thereof;

[0792] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3) or a retro-inverso- form thereof;

[0793] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0794] (iii) a peptoid or N-methyl version of (i) or (ii).

[0795] 2. A MDM2 inhibitor according to numbered embodiment 1 , wherein P comprises:

[0796] Arg or D-Arg at position 1 , or an N-methyl or N-substituted glycine analogue thereof;

[0797] Tyr, Trp, Phe, Leu, He or Vai at position 11 , or a D-form, N-methyl or N-substituted glycine analogue thereof; and / or

[0798] Phe, Trp, Tyr, Leu, He or Vai at position 12, or a D-form, N-methyl or N-substituted glycine analogue thereof. 008849002

[0799] 63

[0800] 3. A MDM2 inhibitor according to numbered embodiment 1 or numbered embodiment 2, wherein P comprises all three of:

[0801] Arg or D-Arg at position 1 , or an N-methyl or N-substituted glycine analogue thereof;

[0802] Tyr, Trp, Phe, Leu, He or Vai at position 11 , or a D-form, N-methyl or N-substituted glycine analogue thereof; and

[0803] Phe, Trp, Tyr, Leu, He or Vai at position 12, or a D-form, N-methyl or N-substituted glycine analogue thereof.

[0804] 4. A MDM2 inhibitor according to any one of the preceding numbered embodiments, wherein the residue at position 4 is Gin, optionally wherein the residue at position 8 is Asp.

[0805] 5. A MDM2 inhibitor according to any one of the preceding numbered embodiments, wherein the residue at position 4 is Aib and the residue at position 8 is Aib.

[0806] 6. A MDM2 inhibitor according to any one of the preceding numbered embodiments, wherein the residues at positions 4 and 7 or at positions 4 and 8 are a pair of residues and whose side chains participate in a covalent bond.

[0807] 7. A MDM2 inhibitor according to numbered embodiment 6, wherein the covalent bond is a disulfide bond, a thioether bond, a lactam bond, a triazole or an all hydrocarbon bond.

[0808] 8. A MDM2 inhibitor according to numbered embodiment 6, wherein the side chains of residues 4) are joined by a scaffold.

[0809] 9. A MDM2 inhibitor according to any one of the preceding numbered embodiments, further comprising one or more heterologous moieties.

[0810] 10. A MDM2 inhibitor according to numbered embodiment 9, wherein the heterologous moiety is linked to a side chain of P at a residue (, or to a N-terminal or C-terminal functional group.

[0811] 11. A MDM2 inhibitor according to numbered embodiment 10, wherein the residue is at position 0 or position 9 of P. 008849002

[0812] 64

[0813] 12. A MDM2 inhibitor according to numbered embodiment 10 or numbered embodiment 11 , wherein the residue is Cys, hCys, or a D-form of either.

[0814] 13. A MDM2 inhibitor according to any one of numbered embodiments 9 to 12, wherein the heterologous moiety is a membrane transit moiety.

[0815] 14. A MDM2 inhibitor according to numbered embodiment 13, wherein the membrane transit moiety comprises a fatty acid, lipid or steroid.

[0816] 15. A MDM2 inhibitor according to numbered embodiment 13, wherein the membrane transit moiety is a cell penetrating peptide.

[0817] 16. A MDM2 inhibitor according to numbered embodiment 15, wherein the cell penetrating peptide forms a fusion protein with P.

[0818] 17. AMDM2 inhibitor according to numbered embodiment 16, wherein the cell penetrating peptide is located N-terminal of the core sequence and is optionally spaced from the N-terminus of the core sequence by a linker peptide.

[0819] 18. An MDM2 inhibitor according to any one of numbered embodiments 15 to 17, wherein the cell penetrating peptide is poly-arginine, poly-D-arginine, GRKKRRQRRR, Grkkrrqrrr, cyclo[GRKKRRQRRR] cyclo[Grkkrrqrrr],

[0820] 008849002

[0821] 65

[0822] 19. AMDM2 inhibitor according to numbered embodiment 18, wherein the cell penetrating peptide is Arg4 w or [D-Arg]4 w, e.g. Args, Argo, [D-Arg]s or [D-Arg]g.

[0823] 20. A MDM2 inhibitor according to any one of the preceding numbered embodiments, wherein the core sequence has the formula: 008849002

[0824] 66

[0825] X1 -X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12 wherein

[0826] XI is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[0827] X2 is selected from Gin, Phe, Tyr, Leu, lie, Gly, Met, Cys, His, Thr, Pro, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[0828] X3 is selected from Pro, Gly, Cys, His, Thr, Gin, Asn and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or a residue

[0829] X4 is selected from lie, Trp, Phe, Tyr, Leu, Vai, Gly, Met, Cys, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof, Aib, or is a residue or

[0830] X5 is selected from Gin, Trp, Phe, Leu, lie, Vai, Met, His, Thr, Pro, Ser and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0831] X6 is selected from Met, Tyr, Leu, lie, Vai, Gly, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N- substituted glycine analogue thereof;

[0832] X7 is selected from lie, Phe, Tyr, Leu, Vai, Met, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue1;

[0833] X8 is selected from Vai, Trp, Phe, Tyr, Leu, lie, Gly, Met, Cys, His, Thr, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, Aib, or is a residue

[0834] X9 is selected from Leu, Trp, Phe, Tyr, lie, Vai, Gly, Met, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0835] X10 is selected from Thr, Phe, Leu, lie, Vai, Gly, Met, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0836] XI I is selected from Tyr, Trp, Phe, Leu, lie, Vai, Gly, Met, Cys, His, Thr, Pro, Gin, Asn, Ser, Glu, Arg and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0837] X12 is selected from Phe, Trp, Tyr, Leu, lie, Vai, Gly, Met, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof; wherein, if X4 is a residue cb then residue X7 or X8 is a residue and vice versa, a maximum of one residue is present, and, when present, the side chains of residues 0 and form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; 008849002

[0838] 67 and wherein the core sequence is:

[0839] (i)

[0840] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1 ) or an all-D form thereof;

[0841] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0842] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[0843] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0844] (iii) a peptoid, N-methyl or retro-inverso version of (i) or (ii).

[0845] 21 . A MDM2 inhibitor according to numbered embodiment 20, wherein:

[0846] X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[0847] X2 is selected from Gin, Phe, Tyr, Leu, He, Gly, Met, Cys, His, Thr, Pro, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0848] X3 is selected from Pro, Gly, Cys, His, Thr, Gin, Asn and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0849] X4 is selected from lie, Trp, Phe, Tyr, Leu, Vai, Gly, Met, Cys, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof, Aib, or is a residue or

[0850] X5 is selected from Gin, Trp, Phe, Leu, lie, Vai, Met, His, Thr, Pro, Ser and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0851] X6 is selected from Met, Tyr, Leu, lie, Vai, Gly, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N- substituted glycine analogue thereof;

[0852] X7 is selected from lie, Phe, Tyr, Leu, Vai, Met, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0853] X8 is selected from Vai, Trp, Phe, Tyr, Leu, He, Gly, Met, Cys, His, Thr, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, Aib, or is a residue 008849002

[0854] 68

[0855] X9 is selected from Leu, Trp, Phe, Tyr, He, Vai, Gly, Met, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0856] X10 is selected from Thr, Phe, Leu, He, Vai, Gly, Met, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0857] X11 is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;

[0858] X12 is selected from Phe, Trp, Tyr, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue and vice versa, a maximum of one residue *4^ is present, and, when present, the side chains of residues <D and *4^ form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[0859] (i)

[0860] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1 ) or an all-D form thereof;

[0861] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0862] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[0863] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0864] (iii) a peptoid, N-methyl or retro-inverso version of (i) or (ii).

[0865] 22. A MDM2 inhibitor according to numbered embodiment 20 or numbered embodiment 21 , wherein:

[0866] X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof; 008849002

[0867] 69

[0868] X2 is selected from Gin, Gly, His, Thr, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0869] X3 is selected from Pro, Gly and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[0870] X4 is selected from He, Trp, Tyr, Leu, Vai, Gly, His, Thr, Gin and Ser, or a D-form, N-methyl, or N- substituted glycine analogue thereof, Aib, or is a residue <P or

[0871] X5 is selected from Gin, His, Thr and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0872] X6 is selected from Met, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0873] X7 is selected from He, Phe, Tyr, Leu, Vai, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue 4L

[0874] X8 is selected from Vai, Phe, Tyr, Leu, lie, Thr, Asn, Ser, Asp and Glu, or a D-form, N-methyl, or N- substituted glycine analogue thereof, Aib, or is a residue *4^

[0875] X9 is selected from Leu, Phe, Tyr, lie, Vai, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0876] X10 is selected from Thr, Gly, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0877] X11 is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;

[0878] X12 is selected from Phe, Trp, Tyr, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue * and vice versa, a maximum of one residue *P is present, and, when present, the side chains of residues and *P form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[0879] (i)

[0880] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof; 008849002

[0881] 70

[0882] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0883] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[0884] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0885] (iii) a peptoid, N-methyl version or retro-inverso form of (i) or (ii).

[0886] 23. A MDM2 inhibitor according to any one of numbered embodiments 20 to 22, wherein:

[0887] XI is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[0888] X2 is selected from Gin, Gly, His, Thr, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0889] X3 is selected from Pro, Gly and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0890] X4 is selected from He, Gly, His, Thr, Gin and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof, Aib, or is a residue or

[0891] X5 is selected from Gin, His, Thr and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0892] X6 is selected from Met, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0893] X7 is selected from He, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue H*;

[0894] X8 is selected from Vai, Thr, Asn, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, Aib, or is a residue

[0895] X9 is selected from Leu, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[0896] X10 is selected from Thr, Gly, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[0897] XI I is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; 008849002

[0898] 71

[0899] X12 is selected from Phe, Trp, Tyr, Leu, He and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue M' and vice versa, a maximum of one residue1is present, and, when present, the side chains of residues and1form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[0900] (i)

[0901] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;

[0902] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0903] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[0904] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[0905] (iii) a peptoid, N-methyl version or retro-inverso form of (i) or (ii).

[0906] 24. A MDM2 inhibitor according to any one of numbered embodiments 20 to 23, wherein the core sequence has the formula:

[0907] X1-Gln-Pro-X4-Gln-X6-X7-X8-X9-Thr-X11-X12 where

[0908] X1 is selected from Arg and D-Arg

[0909] X4 is He, Gin, Aib, or is a residue <t> or

[0910] X6 is selected from Met and Thr, or a D-form thereof; 008849002

[0911] 72

[0912] X7 is He, or is a residue

[0913] X8 is Vai, Asp, Aib, or is a residue T1;

[0914] X9 is Leu, or is a residue

[0915] X11 is selected from Tyr and Leu, or a D-form thereof;

[0916] X12 is selected from Phe and D-Phe.

[0917] 25. A MDM2 inhibitor according to any one of numbered embodiments 20 to 23, wherein the core sequence has the formula:

[0918] X1-Gln-Pro-X4-Gln-X6-X7-X8-X9-Thr-X11-X12-X13 where

[0919] XI is selected from Arg and D-Arg, preferably D-Arg

[0920] X4 is He, Gin, Aib, or is a residue <t> or preferably residue <D;

[0921] X6 is selected from Met and Thr, or a D-form thereof, preferably D-Thr;

[0922] X7 is lie, or is a residue preferably lie;

[0923] X8 is Vai, Asp, Aib, or is a residue 'P, preferably

[0924] X9 is Leu, Gly, Ala, Vai, lie, Pro, Met, Phe, Trp, methyl-phenylalanine or naphthalene;

[0925] XI I is selected from Tyr and Leu, or a D-form thereof, preferably D-Leu;

[0926] X12 is selected from Phe and D-Phe, preferably D-Phe;

[0927] X13 is absent or Phe, Tyr or Trp.

[0928] 26. A MDM2 inhibitor according to claim 25, wherein X9 is selected from the group consisting of Gly, Ala, Vai, lie, Pro, Met, Phe, Trp, methyl-phenylalanine, or naphthalene and / or X13 is selected from the group consisting of Phe, Tyr or Trp.

[0929] 27. A MDM2 inhibitor according to any one of numbered embodiments 20 to 26, wherein the disruptor component P comprises additional sequence N- or C-terminal of the core sequence.

[0930] 28. A MDM2 inhibitor according to numbered embodiment 27, wherein P comprises a residue N- terminal of the core sequence, e.g. at position X0. 008849002

[0931] 73

[0932] 29. A MDM2 inhibitor according to numbered embodiment 28, wherein the residue is Cys, hCys, or a D-form of either.

[0933] 30. A MDM2 inhibitor according to any one of numbered embodiments 20 to 29, wherein P comprises a maximum of one residue t,.

[0934] 31. A MDM2 inhibitor according to any one of the preceding numbered embodiments, wherein the core sequence comprises a sequence selected from:

[0935] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1);

[0936] Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[0937] [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; and

[0938] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe; or a peptoid, N-methyl or retro-inverso version thereof.

[0939] 32. A MDM2 inhibitor according to any one of numbered embodiments 1 to 30, wherein the core sequence comprises a sequence selected from:

[0940] [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Asp-Leu-Thr-[D-Leu]-[D-Phe];

[0941] [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0942] [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Asp-Leu-Thr-[D-Leu]-[D-Phe]; and

[0943] [D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-Leu-Thr-[D-Leu]-[D-Phe]; or a peptoid, N-methyl or retro-inverso version thereof.

[0944] 33. A MDM2 inhibitor according to any one of numbered embodiments 1 to 30, wherein the core sequence comprises a sequence selected from:

[0945] Arg-Gln-Pro-dJ-Gln-Met-lle-MJ-Leu-Thr-Leu-Phe;

[0946] Arg-Gln-Pro-<U-Gln-Met-lle-MJ-Leu-Thr-[D-Leu]-[D-Phe];

[0947] [D-Arg]-Gln-Pro-<U-Gln-[D-Thr]-lle-MJ-Leu-Thr-[D-Leu]-[D-Phe];

[0948] Arg-Gln-Pro-dJ-Gln-Met-lle-MJ-Leu-Thr-Tyr-Phe;

[0949] Arg-GIn-Pro-O-GIn-Met-'+’-Val-Leu-Thr-Leu-Phe;

[0950] Arg-Gln-Pro-(U-Gln-Met- ’-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0951] [D-Arg]-Gln-Pro-(D-Gln-[D-Thr]-i -Val-Leu-Thr-[D-Leu]-[D-Phe]; and 008849002

[0952] 74

[0953] Arg-GIn-Pro- -GIn-Met-'+’-Val-Leu-Thr-Tyr-Phe; where the side chains of residues and MJ form a covalent bond; or a peptoid, N-methyl or retro-inverso version thereof.

[0954] 34. A MDM2 inhibitor according to any one of numbered embodiments 1 to 30, wherein the disruptor component P comprises a sequence selected from:

[0955] ^-Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe; -Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0956] <-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0957] ^-Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe;

[0958] Arg-GIn-Pro-lle-GIn-Met-lle-Val-^-Thr-Leu-Phe;

[0959] Arg-Gln-Pro-lle-Gln-Met-lle-Val-<-Thr-[D-Leu]-[D-Phe];

[0960] [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val- -Thr-[D-Leu]-[D-Phe]; and

[0961] Arg-GIn-Pro-lle-GIn-Met-lle-Val-^-Thr-Tyr-Phe; where the side chain of the residue forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof.

[0962] 35. A MDM2 inhibitor according to any one of numbered embodiments 1 to 30, wherein the disruptor component P comprises a sequence selected from:

[0963] <-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Asp-Leu-Thr-[D-Leu]-[D-Phe]; - [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; - [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Asp-Leu-Thr-[D-Leu]-[D-Phe]; - [D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-Leu-Thr-[D-Leu]-[D-Phe];

[0964] [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Asp-<-Thr-[D-Leu]-[D-Phe];

[0965] [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val- -Thr-[D-Leu]-[D-Phe];

[0966] [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Asp-<-Thr-[D-Leu]-[D-Phe]; and

[0967] [D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib- -Thr-[D-Leu]-[D-Phe]; 008849002

[0968] 75 where the side chain of the residue £ forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof.

[0969] 36. A MDM2 inhibitor according to any one of numbered embodiments 1 to 30, wherein the disruptor component P comprises a sequence selected from:

[0970] ^-Arg-GIn-Pro-O-GIn-Met-lle-'+'-Leu-Thr-Leu-Phe;

[0971] <-Arg-Gln-Pro-O-Gln-Met-lle-^-Leu-Thr-[D-Leu]-[D-Phe];

[0972] <-[D-Arg]-Gln-Pro-ct>-Gln-[D-Thr]-lle-^-Leu-Thr-[D-Leu]-[D-Phe];

[0973] (-Arg-GIn-Pro-cb-GIn-Met-lle-^P-Leu-Thr-Tyr-Phe;

[0974] (-Arg-GIn-Pro-cb-GIn-Met-^P-Val-Leu-Thr-Leu-Phe;

[0975] <-Arg-Gln-Pro-0-Gln-Met-^-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0976] <-[D-Arg]-Gln-Pro-ct>-Gln-[D-Thr]-^-Val-Leu-Thr-[D-Leu]-[D-Phe];

[0977] (-Arg-GIn-Pro-cb-GIn-Met-^P-Val-Leu-Thr-Tyr-Phe;

[0978] Arg-Gln-Pro-<t>-Gln-Met-lle-'4J-£-Thr-Leu-Phe;

[0979] Arg-Gln-Pro-<D-Gln-Met-lle-^-<-Thr-[D-Leu]-[D-Phe];

[0980] [D-Arg]-Gln-Pro-<D-Gln-[D-Thr]-lle-^-<-Thr-[D-Leu]-[D-Phe];

[0981] Arg-Gln-Pro-<t>-Gln-Met-lle-'4J-£-Thr-Tyr-Phe;

[0982] Arg-Gln-Pro-d>-Gln-Met-lP-Val-£-Thr-Leu-Phe;

[0983] Arg-Gln-Pro-<D-Gln-Met-iP-Val-<-Thr-[D-Leu]-[D-Phe];

[0984] [D-Arg]-Gln-Pro-<b-Gln-[D-Thr]-MJ-Val <-Thr-[D-Leu]-[D-Phe]; and

[0985] Arg-GIn-Pro-O-GIn-Met-'+’-Val-^-Thr-Tyr-Phe; where the side chains of residues ct> and form a covalent bond; and where the side chain of the residue ( forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof. 008849002

[0986] 76

[0987] 37. A MDM2 inhibitor according to any one of the preceding numbered embodiments, having the formula

[0988] Z-L-P where

[0989] Z is a cell penetrating peptide;

[0990] P is the disruptor component; and

[0991] L is a linker peptide sequence (e.g. of 1-10 amino acids, e.g. of 1-5 amino acids), or represents a bond between Z and P; or a peptoid, N-methyl or retro-inverso version thereof.

[0992] 38. A MDM2 inhibitor according to numbered embodiment 37, having the formula

[0993] Y1 -Z-L-P- Y2 where

[0994] Y1 is H, Ac cr a heterologous moiety (e.g. H or Ac);

[0995] Z is a cell penetrating peptide;

[0996] P is the disruptor component;

[0997] L is a linker peptide sequence (e.g. of 1-10 amino acids, e.g. of 1-5 amino acids), or represents a bond between Z and P; and

[0998] Y2 is OH, NH2 or a heterologous moiety (e.g. OH or NH2).

[0999] 39. A MDM2 inhibitor according to any one of numbered embodiments 1 to 36, having the formula

[1000] Y1-P-Y2 where

[1001] Y1 is H, Ac or a heterologous moiety;

[1002] P is the disruptor component; and

[1003] Y2 is OH, NH2 or a heterologous moiety (e.g. OH or NH2).

[1004] 40. A MDM2 inhibitor according to any one of the preceding numbered embodiments, comprising the sequence:

[1005] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe; 008849002

[1006] 77

[1007] (Stearoyl)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe;

[1008] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe;

[1009] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Tyr]-[D-Phe];

[1010] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Leu-Phe;

[1011] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1012] [D-Arg]8-Cys-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1013] Cys(-Ac-[D-Arg]9-NH2)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1014] [D-Cys](-Ac-[D-Arg]9-NH2)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1015] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1016] Cys-(-C12-cCPP-C)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1017] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1018] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-Leu-Thr-[D-Leu]-[D-Phe];

[1019] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-hCys-Gln-[D-Thr]-lle-hCys-Leu-Thr-[D-Leu]-[D-Phe];

[1020] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Pra-Gln-[D-Thr]-lle-Abu(N3)-Leu-Thr-[D-Leu]-[D-Phe]; or

[1021] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Cys-Gln-[D-Thr]-lle-Cys-Leu-Thr-[D-Leu]-[D-Phe]-NH2or a peptoid, N-methyl or retro-inverso version thereof.

[1022] 41 . A MDM2 inhibitor selected from:

[1023] Ac-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe-NH2;

[1024] (Stearoyl)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe-NH2(DRx-97-S);

[1025] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe -NH2(DRx-97-R);

[1026] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Tyr]-[D-Phe]-NH2(DRx-97D-R);

[1027] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Leu-Phe-NH2(DRx-98R);

[1028] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-98D-R);

[1029] Ac-[D-Arg]8-Cys-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-990);

[1030] Ac-Cys(-Ac-[D-Arg]9-NH2)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-991 );

[1031] Ac-[D-Cys](-Ac-[D-Arg]9-NH2)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx- 992);

[1032] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(7175);

[1033] Cys-(-C12-cCPP-C)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(7176); 008849002

[1034] 78

[1035] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(1724);

[1036] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-Leu-Thr-[D-Leu]-[D-Phe]-NH2(1211 );

[1037] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-hCys-Gln-[D-Thr]-lle-hCys-Leu-Thr-[D-Leu]-[D-Phe]-NH2(3276);

[1038] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Pra-Gln-[D-Thr]-lle-Abu(N3)-Leu-Thr-[D-Leu]-[D-Phe]-NH2(3277); and

[1039] Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Cys-Gln-[D-Thr]-lle-Cys-Leu-Thr-[D-Leu]-[D-Phe]-NH2(3275); or a peptoid, N-methyl or retro-inverso version thereof.

[1040] 42. A MDM2 inhibitor according to any one of the preceding numbered embodiments for use in a method of medical treatment.

[1041] 43. A MDM2 inhibitor according to any one of numbered embodiments 1 to 41 for use in a method of treatment of a disease or condition selected from cancer, inflammatory disease, dementia or a neurodegenerative disease, nephropathy, or heart or cardiovascular disease.

[1042] 44. A MDM2 inhibitor according to numbered embodiment 43, wherein the disease or condition is cancer.

[1043] 45. A MDM2 inhibitor according to numbered embodiment 44, wherein the cancer is neuroblastoma, a myeloproliferative neoplasm (e.g. polycythemia vera or myelofibrosis), leukaemia (e.g., acute myeloid leukaemia and subtypes thereof), lung cancer, colorectal cancer (e.g., poorly differentiated colorectal cancer), osteosarcoma, melanoma, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), prostate cancer (e.g., neuroendocrine prostate cancer), rhabdomyosarcoma, or glioma (e.g., paediatric high-grade glioma).

[1044] 46. A MDM2 inhibitor for use according to numbered embodiment 45, wherein the acute myeloid leukaemia subtype is acute promyelocytic leukaemia.

[1045] 47. A MDM2 inhibitor for use according to any one of numbered embodiments 44 to 46, wherein the method of treatment further comprises administering a differentiation-inducing agent to a subject.

[1046] 48. A MDM2 inhibitor for use according to numbered embodiment 47, wherein the differentiationinducing agent is selected from the group consisting of retinoic acid and retinoic acid derivatives, arsenic 008849002

[1047] 79 trioxide (ATO), cAMP, sodium butyrate, cytokines, dimethyl sulfoxide, active form vitamin D(3), peroxisome proliferator-activated receptorgamma, 12-Myristate 13-acetate (PMA), hexamethylene-bis- acetamide, butyric acid, and vesnarinone.

[1048] 49. A MDM2 inhibitor for use according to numbered embodiment 48, wherein the retinoic acid derivate is all-trans retinoic acid (ATRA), 13 cis-retinoic acid (13-cis RA) or 9-cis retinoic acid.

[1049] 50. A MDM2 inhibitor for use according to any one of numbered embodiments 47 to 49, wherein the differentiation-inducing agent is administered simultaneously as the MDM2 inhibitor or wherein the differentiation-inducing agent is administered separately to the MDM2 inhibitor.

[1050] 51. A MDM2 inhibitor for use according to numbered embodiment 43, wherein the inflammatory disease is an autoimmune disease, e.g. rheumatoid arthritis, systemic lupus erythaematosus (SLE), pancreatitis or gastritis.

[1051] 52. A MDM2 inhibitor for use according to numbered embodiment 43, wherein the dementia or neurodegenerative disease is, or is associated with, for example, fragile X syndrome, Parkinson’s disease or Alzheimer’s disease.

[1052] 53. A MDM2 inhibitor for use according to numbered embodiment 43, wherein the nephropathy is autosomal dominant polycystic kidney disease, renal fibrosis or diabetic nephropathy.

[1053] 54. A MDM2 inhibitor for use according to numbered embodiment 43, wherein the cardiovascular disease is myocardial infarction or atherosclerosis.

[1054] 55. A composition comprising an MDM2 inhibitor any one of numbered embodiments 1 to 41 and a differentiation-inducing agent for use in the treatment of cancer.

[1055] 56. A composition for use according to numbered embodiment 55, wherein the differentiationinducing agent is selected from the group consisting of retinoic acid and retinoic acid derivatives, arsenic 008849002

[1056] 80 trioxide (ATO), cAMP, sodium butyrate, cytokines, dimethyl sulfoxide, active form vitamin D(3), peroxisome proliferator-activated receptor gamma, 12-Myristate 13-acetate (PMA), hexamethylene-bis- acetamide, butyric acid, and vesnarinone.

[1057] 57. A composition for use according to numbered embodiment 56, wherein the retinoic acid derivate is all-trans retinoic acid (ATRA), 13 cis-retinoic acid (13-cis RA) or 9-cis retinoic acid.

[1058] 58. A composition for use according to any one numbered embodiments 55 to 57, wherein the cancer is neuroblastoma, a myeloproliferative neoplasm (e.g. polycythemia vera or myelofibrosis), leukaemia (e.g., acute myeloid leukaemia and subtypes thereof), lung cancer, colorectal cancer (e.g., poorly differentiated colorectal cancer), osteosarcoma, melanoma, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), prostate cancer (e.g., neuroendocrine prostate cancer), rhabdomyosarcoma, or glioma (e.g., paediatric high-grade glioma).

[1059] 59. A composition for use according to any one numbered embodiments 55 to 57, wherein the cancer is neuroblastoma, leukaemia (e.g., acute myeloid leukaemia and subtypes thereof), colorectal cancer (e.g., poorly differentiated colorectal cancer), osteosarcoma, liver cancer (e.g., hepatocellular carcinoma), prostate cancer (e.g., neuroendocrine prostate cancer), rhabdomyosarcoma, or glioma (e.g., paediatric high-grade glioma).

[1060] 60. A composition for use according to numbered embodiment 58 or 59, wherein the acute myeloid leukaemia subtype is acute promyelocytic leukaemia.

[1061] 61. A pharmaceutical composition comprising a MDM2 inhibitor according to any one of numbered embodiments 1 to 41 , optionally in combination with a pharmaceutically acceptable excipient.

[1062] 62. The pharmaceutical composition according to numbered embodiment 61, wherein the pharmaceutical composition further comprises a differentiation-inducing agent. 008849002

[1063] 81

[1064] Examples

[1065] Materials and Methods

[1066] Antibodies and Chemicals

[1067] Primary antibodies included GST-HRP (1:5000, Sigma, A7340), GAPDH (WB - 1 :3000, Millipore, MAB374), p53 (WB - 1:1000, Santa Cruz, sc-126),P21 WAFI / CIPI (Western Blot (WB) - 1:1000, Cellular Signaling Technology, 2947), MDM2 (WB - 1 :500, Cellular Signaling Technology, ), MDM2 (ICC / PLA - 1:50, Abeam, ab216895), MDMX (WB - 1 :1000, ICC / PLA - 1:250, Sigma, HPA048821), Caspase 3 (WB - 1 :1000, Cellular Signaling Technology, 9662), Cleaved PARP (WB - 1 :1000, Cellular Signaling Technology, 5625), HA-tag (WB - 1 :500, ICC / PLA - 1 :200, Cellular Signaling Technology, 2367), Myc- Tag (WB - 1 :500, ICC / PLA - 1 :200, Cellular Signaling Technology, 2276), MYCN (WB - 1 :3000, Proteintech, 10159-2-AP), c-MYC (WB - 1 :6000, Proteintech, 10828-1-AP), -actin (WB - 1 :2000, Santa Cruz, sc-47778), APC-Cy™7 Mouse Anti-Human CD11 b (FC - 1 :25, BD, 557754), APC anti-human CD14 Antibody (FC - 1 :25, BioLegend, 325608). IRDye (LI-COR) secondary antibodies included 800CW Donkey anti-Rabbit IgG (1 :10,000, 926-32213) and 680RD Donkey anti-mouse IgG (1 :10,000, 926- 68072). Alexa Fluor secondary antibodies included Donkey anti-mouse 647nm (1 :500, ThermoFisher Scientific, A-31571 ) and Donkey anti-rabbit 488nm (1 :500, ThermoFisher Scientific, A-48269). Antibodies were diluted in Intercept T20 TBS antibody diluent (LI-COR). Stock concentrations of Idasanutlin [10 mM], ATRA [50 mM], and all DRx-peptides [1-10 mM] were diluted in 100% DMSO.

[1068] Peptide Array

[1069] Peptide array experiments were performed by automatic SPOT synthesis as described [REF]. Human MDM2 / MDMX peptides were synthesised onto continuous cellulose membrane supports via 9- fluorenylmethyloxycarbonyl chemistry (Fmoc) using the MultiPep 2 Robot (CEM). A far western blot approach was utilised to detect GST-fusion MDM2 (aa428-491) RING-C-terminal domain protein binding (gifted from Prof. Danny Huang research group, CRUK Beatson Glasgow). Peptides arrays were (i) blocked for 1 hour at room temperature (2.5% milk in 1X TBS), (ii) incubated overnight at 4°C in [0.1 pM] MDM2 (200 mM NaCI, 50 mM Tris, 5 mM DTT, 5% Glycerol, protease cocktail inhibitor tablet (Roche), pH 7.4), (iii) incubated for 1 hour at room temperature in aGST-HRP primary antibody, and (iv) visualised via ECL detection utilising the C-Digit Blot Scanner (LI-COR). GST only was used as a negative protein control. Peptide arrays were washed three times for 10 minutes with 1X TBS-T between each protein / antibody incubation step. Gentle agitation of peptide arrays occurred for each incubation / wash step. Densitometry was carried out to quantify peptide binding signal presented in Figure 2, where control peptide(s) were averaged and subsequently normalised to 100%. The other peptides therefore represent a % difference of normalised control peptide.

[1070] Fluorescent Ligand-Based Binding Assay 008849002

[1071] 82

[1072] A fluorescent based target engagement assay was utilised to measure the binding affinity of MDM2- derived peptides (N-terminal 5-FITC labelled) with human GST-fusion MDM2 (aa428-491 ) RING-C- terminal domain protein OR GST-fusion MDMX (aa428-490) RING-C-terminal domain. Glutathione coated wells of a pre-blocked, black, clear bottom, 96-well plate (15340 - ThermoFisher Scientific) were incubated with MDM2, MDMX, or GST-only protein (50 ng / well) and incubated overnight at 4°C. Wells were then incubated with increasing concentrations (11 -point dose response) of FITC-labelled peptide (0.05 nM - 3 pM) for 2 Hours at room temperature. Excess protein I peptide were removed following each incubation step by washing 3 times in 1X TBS-T. Protein and peptides were diluted in protein buffer (200 mM NaCI, 50 mM Tris, 5 mM DTT, 5% Glycerol, protease cocktail inhibitor tablet (Roche), pH 7.4). FITC- peptide binding to target protein was measured using a Tristar 5 multimode microplate reader (Berthold Technologies). Binding affinities were measured via non-linear regression analysis (GraphPad Prism 8.0).

[1073] In Vitro MDM2-p53 Ubiquitination Assay

[1074] To evaluate MDM2 disruptor peptides ability to attenuate MDM2 E3 ligase activity, a cell-free in vitro MDM2-p53 ubiquitination assay kit was utilised (R&D systems, K-200B). Ubiquitination assay was carried out as per manufacturer’s instructions, with the inclusion of an extra step involving co-incubation of GST- MDM2 enzyme with MDM2 disruptor peptide (i.e. , simultaneous addition, not pre- or post-addition). Using a p53 monoclonal primary antibody (1 :1000, Santa Cruz, sc-126), MDM2-mediated p53 ubiquitination was measured via western immunoblotting (see below).

[1075] Cell Culture

[1076] All cell lines were cultured in media supplemented with 2 mM L-glutamine (v / v), 100 U / l Pen-Strep (v / v) and 10% FBS (v / v) (i.e., for 20% FBS, Kasumi-1 cells) and grown in a humidified environment with 5% CO2 at 37°C. PANC1 (ATCC - CRL-1469), U2-OS (ATCC HTB-96), HCT116 (ATCC - CCL-247), A549 (ATCC - CCL-185), SK-N-F1 (ATCC - CCL-2142), IMR-90 (ATCC - CCL-186) and HEK293 (ATCC - CRL-1573) were cultured in complete DMEM. MM415 (Sigma - 10092319), BxPC3 (CRL-1687), SK-N- Be(2), SK-N-FI, NGP, N_N20R1 , N_M5R1 , Kasumi-1 , Mono-Mac-1 , THP-1 , U937, HL-60, OCI-AML-3, MV4-11 , MOLM-13 and THP-1 were cultured in complete RPMI.

[1077] Immunocytochemistry

[1078] U2-OS, A549, HCT116 p53wild-typeand HCT116 p53mutantcells were seeded at 0.3 x 105cells per well of a 12-well plate containing a sterilised 0.13-0.17mm glass coverslip in complete DMEM and incubated overnight. Cells were fixed in 4% paraformaldehyde (Sigma) for 15 minutes at room temperature. Cell membranes were then permeabilised with 0.1% Triton X100 (sigma) for 4 minutes at room temperature. Blocking was then carried out for 1 hour at room temperature with 10% donkey serum, 1 % BSA in PBS. Respective primary antibodies were then diluted in 5% donkey serum, 1% BSA in PBS and cells co- 008849002

[1079] 83 incubated overnight at 4°C. Secondary Alexa Fluor antibodies were then simultaneously co-incubated for 1 hour at room temperature. Cells were washed three times in PBS between each of the above steps. Finally, coverslips were then mounted onto glass slides with Prolong Gold Antifade Mountant with DAPI (ThermoFisher Scientific, P36941). Cells were imaged using a Zeiss confocal microscope (63X oil immersion objective lens).

[1080] In situ analysis of the MDM2 dimerisation was assessed via Duolink™ Proximity Ligation Assay (Sigma). MDM2-MDMX endogenous heterodimerisation was assessed in A549 cells. Homodimerisation of full- length endogenous MDM2 with transfected MDM2-(428-C)-HA protein and heterodimerisation of full- length endogenous MDM2 with transfected MDMX-(426-C)-Myc protein was assessed in U2-OS cells. In these cases, mammalian DNA constructs (gifted by Prof. Karen Vousden’s research group, Francis Crick Institute London) of MDM2-(435-C)-HA or MDMX-(428-C)-Myc (pcDNA3.1+) were transiently transfected (2 pg DNA, 48 hours) in U2-OS cells utilising Lipofectamine 3000 as per manufacturer’s instructions (Invitrogen). Cells were then washed three times in PBS, fixed, and membranes permeabilised as per above ICC protocol. Following this, cells were blocked for 1 hour at 37°C with Duolink® blocking buffer. Primary antibodies raised in different species (mouse and rabbit) were used to detect proteins of interest (i.e. , MDM2 and MDMX), diluted in Duolink® antibody diluent and incubated overnight at 4°C. PLA probes (oligonucleotide-labelled secondary antibodies; PLUS and MINUS) were then introduced to recognise primary antibodies, where hybridization between oligos occurs if probes are <40nm apart. Complete circularisation of oligos by ligase forms a closed circular DNA template that is subsequently amplified by DNA polymerase, a process known as rolling circle amplification (RCA). Hybridisation of amplified oligos with complementary fluorescently labelled oligos (594 Aex / 624 Aem) allow for localisation of the PLA signal (discrete red spots), indicative of heterodimer formation. Cell nuclei were stained with Prolong Gold Antifade Mountant with DAPI (ThermoFisher Scientific, P36941). PLA signal was detected using a Zeiss confocal microscope with a 63X oil immersion objective. Quantification of identified PLA signals were measured using Image J and analysed on GraphPad Prism 8.0.

[1081] Western Immunoblottinq

[1082] Protein lysates were harvested using lysis buffer (25mM Tris, 150mM NaCI, 0.1mM EDTA, 1% NP-40, 5% glycerol, pH 7.4) supplemented with protease and phosphatase inhibitors (Roche). Protein samples were diluted in SDS sample buffer (10% SDS, 300mM Tris-HCI, 0.05% bromothymol blue, 10% 0- mercaptoethanol) and boiled for 10 minutes at 70°C. Proteins were resolved via SDS-PAGE using 4-12% Bis-Tris gels (NuPAGE), transferred to nitrocellulose membranes (GE Healthcare). In cases where total protein was used as a normalisation control (instead of a housekeeper protein, such as GAPDH), Revert™ Total Protein 700nm IR-Stain (LICOR) was used as per manufacturer’s instructions. Membranes were blocked in Intercept TBS blocking buffer (LI-COR) and incubated overnight in primary antibody at 008849002

[1083] 84

[1084] 4°C. Membranes were then incubated in IRDye secondary antibody (1 :10,000, LI-COR) for 1 hour at room temperature and immunoreactive bands visualised using the Odyssey CLx imaging system (Ll- COR). Densitometry of immunoreactive bands was carried out using Image J software.

[1085] In Vitro

[1086] HEK293 and IMR-90 cells (0.5x104) were seeded in wells of a clear bottom 96-well plate containing complete DMEM (2% FBS, 2mM L-glutamine, 100 U / l Pen-Strep). Cells were allowed to grow overnight before treatment with DRx-098D-R or Vehicle (DMSO) for 24 hours. Following treatment duration, cell viability was measured using CellTiter Gio® 2.0 cell viability assay (Promega; G7570) as per manufacturer’s instructions.

[1087] In Vitro Cell Viability Assay - CellTiter Gio® 2.0

[1088] Utilising the CellTiter Gio® 2.0 cell viability assay (Promega; G7570) THP-1 (20k / well), MOLM-13 (40k / well), U2-OS (5k / well), SK-N-Be(2) (5k / well), SK-N-FI (5k / well), NGP (5k / well), N_N20R1 (5k / well), N_M5R1 (5k / well), HCT116P53wild type(5k / well) and HCT116 p53 ' (5k / well) cell viability was assessed following treatment with the respective peptide / compound. Cells were seeded in wells of a white coated, clear bottom 96-well plate containing low serum (2% FBS) or high serum (10% FBS) media. Cells were left overnight prior to treatment for 24 - 120 hours. Cell viability was then measured as per manufacturer’s instructions.

[1089] In Vitro Cell Viability Assay - MTS

[1090] Utilising the CellTiter 96® Aqueous One Solution (MTS) cell viability assay (Promega; G3582) HCT116 (5k / well), A549 (5k / well), U2-OS (5k / well), BxPC3 (5k / well), MM415 (5k / well), SK-N-FI (5k / well) and PANC1 (5k / well) cell viability was assessed following treatment with DRx-098D-R. Cells were seeded in wells of a clear bottom 96-well plate containing low serum (2% FBS) media (DMEM: U2-OS, HCT116, A549, SK-N-FI, PANC1 ; RPMI: BxPC3, MM415). Cells were left overnight prior to treatment for 24-48 hours. MTS reagent was added for 2 hours, and cell viability was then measured as per manufacturer’s instructions.

[1091] In Vitro Cell Viability Assay - Resazurin

[1092] Utilising a Resazurin (Sigma) cell viability assay (cell-permeable dye that, when reduced intracellularly in metabolising cells, produces a fluorescent by-product - Resorufin), TP53 mutant acute myeloid leukaemia cell lines Kasumi-1 , Mono-Mac-1 , THP-1 , U-937, HL-60 relative viability was determine following 72 Hrs treatment with DRx-992, Idasanutlin, DRx-992-C or vehicle. Cells were seeded in wells of a black, clear bottom 96-well plate containing appropriate complete (10% FBS) RPMI medium. Fluorescent Resazurin reagent was added for 3 hours, and cell viability was then measured as per manufacturer’s instructions. 008849002

[1093] 85

[1094] Real-Time Cellular

[1095] Label-free cellular growth of human cancer cell lines were measured using the xCELLigence real-time cellular analysis platform (RTCA, Roche Applied Science) as per manufacturer’s instructions. 96-well E- plates, designed with gold biosensors on the bottom of the plate, were utilised to measure cellular impedance within each well. Cellular impedance measures relative cell growth in real-time (measured as ‘cell index’ or Cl). Cell index increases as cells become adherent, proliferate and / or grow in size (and vice versa). For cellular growth analysis, HCT116 cells were seeded at 1 x 104cells per well, and A549 seeded at 0.25 x 104per well. Following this, cells were allowed to adhere for at least 18 hours. Cells were then treated with the appropriate concentration of drug for up to 72 hours and cell index was monitored every 15 minutes. Cell index Is normalised to treatment timepoint and the rate of growth (i.e., slope of normalised Cl curve) analysed via linear-regression analyses (GraphPad Prism 8.0).

[1096] Annexin V Assay

[1097] HCT116 TP53 wild-type I SK-N-Be(2) cells were seeded at 5 x 103and THP-1 at 2 x 104per well of a white, clear-bottom 96-well plate and incubated overnight. Cells were then treated with DRx-097A-R [3 pM], DRx-098D-R [3 or 5 pM], DRx-992 [3 pM], DRx-992-C [3 pM], Idasanutlin or Vehicle (0.25% DMSO) for 6 Hrs or 24 Hrs. Following treatments, Annexin V levels were measured utilising the RealTime-Glo™ Annexin V Apoptosis luminescence-based assay (Promega, JA1000) as per manufacturer’s instructions. Luminescent Annexin V levels were measured via a Tristar 5 multimode microplate reader (Berthold Technologies).

[1098] RNA sequencing

[1099] HL-60 cells were seeded at 0.2 x 106cells / mL and treated with vehicle (0.1% DMSO), DRx-992-C [3 pM], or DRx-992 [3 pM] for 6 and 24 hrs (N = 4). Total RNA was extracted from 0.5 x 106cells using the RNeasy kit (QIAGEN, #74106) as per the manufacturer’s protocol. Library preparation and paired-end mRNA sequencing was performed on an Illumina NovaSeq X Plus Series (PE150) by Novogene. Raw FASTQ reads were trimmed using Trimmomatic (vO.38.1) and quality control performed using FASTQC (v0.74) in Galaxy. Trimmed reads were then aligned to the human genome (hg38) using HISAT2 (v2.2.1 ) and aligned reads mapped to genes and counted using featurecounts (v2.0.1 ), also in Galaxy. Subsequent analysis was performed with R Studio (v2025.05.01 ), including differential expression analysis of read counts using DESeq2 (v1.40.1 ). Read counts of less than 10 averaged across all samples were excluded from downstream analysis and gene expression was represented by Z-score of filtered counts. Genes were considered significantly upregulated or downregulated if adjusted p value (p adj.) < 0.05 and Log2 fold change (Log2 FC) was > 1 or <-1 , respectively. Gene set enrichment analysis (GSEA) was performed with the gseGO tool within clusterProfiler (v4.8.3).

[1100] Flow 008849002

[1101] 86

[1102] HL-60 cells were treated for 72 hrs with vehicle (0.1% DMSO), DRx-992-C [3 pM], or DRx-992 [3 pM] and each day subjected to CD11b / CD14 co-staining with Annexin / DAPI. For combination treatments, HL-60 and MOLM-13 were treated with ATRA [10 / 100 or 100 / 1000 nM] and DRx-992 [2, 3, 4 pM] alone or in combination for 48 hrs. Cells were washed 1x in 2% FBS PBS before 30 min incubation at 4 °C with CD11b and CD14 antibodies. Subsequently, cells were washed in 1X HBSS (Gibco, 14025092) before 15 min incubation at room temperature with Annexin and DAPI. Cells were detected using a BD FACSCanto II flow cytometer and analysed by FlowJo software (v10.10.0), quantifying the percentage of CD11b+ and CD14+ within the live (Annexin-ZDAPI-) population.

[1103] Cell morphology analysis

[1104] Following 72 hr vehicle, DRx-992-C and DRx-992 treatment as described, cells were spun using a Thermo Scientific Cytospin 4 centrifuge for 5 mins at 750 rpm. The slides were then stained using the Rapid-Chrome™ Kwik-Diff™ Staining Kit (Epredia, #9990702) as per manufacturer’s instructions. Briefly, slides were sequentially dipped five times in Kwik-Diff™ solution 1 (fixative), 2 (eosin), 3 (methylene blue), and finally dH2<D before air-drying and mounting with coverslips. Slides were imaged using an EVOS™ XL Core brightfield microscope at 40X magnification.

[1105] Statistical Analysis

[1106] Data were analysed using an unpaired t test or a one-way ANOVA test with follow up Dunnett’s or Tukey’s multiple comparison analysis. Data represented as MEAN ± SEM from > 3 replicates were determined significant by a p value < 0.05. All statistical analyses were carried out using GraphPad Prism 8.0 software. For RNA-seq data, the statistical outputs generated from DESeq2 were utilised to indicate statistical significance.

[1107] Compounds 008849002

[1108] 87 008849002

[1109] 88 008849002

[1110] 89 008849002

[1111] 90 008849002

[1112] 91 008849002

[1113] 92 008849002

[1114] 93 008849002

[1115] 94

[1116] Results and Discussion

[1117] To identify a rational core peptide sequence for subsequent MDM2 dimerisation disruptor development, peptide array analysis of the MDM2 RING - C-terminal dimerisation interface was carried out (Figure 1 ). Arrays were incubated with GST-fusion human recombinant MDM2 RING - C-terminal protein (GST - MDM2(428-491 )), highlighting strongest MDM2 binding signal to the MDM2 12mer R479-Q-P-l-Q-M-l-V-L- T-Y-F490peptide. Data indicates that removal of the C-terminal Proline 491 and N-terminal N472-K-P-C-P- V-C478region enhances MDM2 peptide’s ability to bind GST-MDM2(428-491 ) protein. These data were unexpected, particularly as C-terminal proline is a known contact residue in MDM2 homodimerisation and heterodimerisation with MDMX. Based on existing 3D X-ray crystallography structures of MDM2 (e.g., PDB: 5MNJ, data not shown), N472-C478 and P491 possess no secondary structure (i.e. , random coil), meaning the 12mer R479-Q-P-l-Q-M-l-V-L-T-Y-F490peptide possesses a higher overall percentage of secondary structure (M484 - Y490 is made up of a -strand) compared to 19mer N479-K-P-C-P-V-C-R-Q- P-l-Q-M-l-V-L-T-Y-F490and 20mer N479-K-P-C-P-V-C-R-Q-P-l-Q-M-l-V-L-T-Y-F-P491(Figure 1 ). R479 - F490 was therefore selected as a core peptide sequence for further optimisation as a potential MDM2 dimerisation disruptor.

[1118] To determine how incorporation of single point substitutions would affect MDM2 binding to the selected core peptide sequence, each residue was sequentially substituted with every other canonical L-amino acid. Of the 240 peptides assessed, 50 maintained GST-MDM2(428-491 ) binding signal within -15% of control R479 - F490 peptide, as shown in Figure 2 (control peptide binding signal was normalised to 100%). Five substitutions generated a peptide with >25% higher GST-MDM2(428-491 ) binding signal than control. Said peptides all possess a point substitution at Y489, whereby hydrophobic amino acids 008849002

[1119] 95

[1120] Leucine, Isoleucine, Phenylalanine, Valine and Tryptophan all increase GST-MDM2(428-491) binding signal. Of these peptides, the Y489L substitution led to the highest % GST-MDM2(428-491) binding signal (i.e. , 66.7% binding increase vs. control peptide, Figure 2).

[1121] To evaluate the ability of potential MDM2 dimerisation disruptor peptides to bind MDM2, a set of MDM2- derived peptides were synthesised including the core peptide sequence identified in Figure 1 (DRx-097) and the strongest binding peptide in Table 2 (DRx-098). Derivatives of these two peptides were also synthesised containing D-Tyr / D-Phe (DRx-097D) or D-Leu / D-Phe (DRx-098D) in place of L-Tyr489 / L- Phe490, and a negative control peptide containing two substitutions that (individually) have been found to ablate GST-MDM2(428-491) binding signal (data not shown), i.e. R479A and F490D (DRx-097A). All peptides possess an N-terminal FITC label (C-terminal FITC labelling was considered undesirable due to the significant MDM2 / MDMX contacts made by residues at or near the C-terminus) and are C-terminally amidated.

[1122] All peptides were co-incubated [0.05 - 3 pM] with immobilised GST-MDM2(428-491) protein and binding curves generated for DRx-097F (Kd = 0.88 pM), DRx-097D-F (Kd = 0.85 pM), DRx-098-F (Kd = 0.71 pM), DRx-098D-F (Kd = 0.77 pM) (Figure 3A-B). No binding curve was generated for DRx-097A-F (Kd > 3 pM) (Figure 3). Data indicates that point substitutions with canonical L-amino acids or D-isomer amino acids does not negatively impact peptide ability to bind MDM2 (i.e., relative binding affinities were non- significantly different, P > 0.05). DRx-098D-F, but not DRx-097A-F, directly bound to GST-MDMX(428- 490) protein (Kd = 0.29 pM) (Figure 3C). Therefore, it can be assumed that DRx-097F, DRx-097D-F and DRx-098-F are also likely to bind GST-MDMX(428-490) protein.

[1123] Given the high % hydrophobicity of these MDM2-derived peptides (>50%), it was assumed that their innate ability to penetrate the cell membrane would be poor. Consequently, as MDM2 and MDMX are intracellular targets, a further set of peptides were synthesised, derivatised with either stearic acid (octadecanoic acid) or D-isomer nona-arginine (D-R9) as cell-penetrating moieties to enhance the cellpermeability of DRx-097, DRx-097D, DRx-098 and DRx-098D. The cell penetrating moieties were located at the peptides' N-terminus (same rationale as FITC labelling). Both cell-penetrating moieties represent highly efficient and well-validated approaches to enhancing cell-permeability and are easily synthesised by standard chemical manufacturing processes, demonstrating good safety profiles (i.e., considered to have high clinical developability). Peptide cyclisation was also assessed as another potential approach to enhancing peptide permeability (as well as stability). DRx-097C represents a head-to-tail cyclic iterative of DRx-097. To mitigate the risk that cyclisation does not enhance intracellular delivery by itself, DRx-097C- R was also synthesised and represents a head-to-tail cyclic peptide with a D-R9 conjugated via a non- cleavable thioether linker at He482Cys (i.e., at a non-essential residue within the peptide’s sequence). Cell-permeability of negative control peptide DRx-097A-R is also enabled through D-R9.

[1124] MDM2 E3-ligase activity is enabled by its ability to dimerise. Thus, the relevant peptides were assessed in a cell-free biochemical MDM2 E3-ligase activity assay (Figure 4). Utilising MDM2-mediated p53 008849002

[1125] 96 ubiquitination as a marker of relative MDM2 E3-ligase activity, all peptides markedly downregulated the levels of ubiquitinated p53 protein expression (Figure 4A). Cyclic peptides (DRx-097C / 097C-R) were less effective than the linear peptides, suggesting head-to-tail cyclisation does not enhance on-target activity. All D-R9-containing peptides (DRx-097 / 097D / 098 / 098D) were evaluated more comprehensively via a 6- point dose response curve [0.001 - 25 pM] and compared with respective D-R9 containing negative control peptide (DRx-097A-R) (Figure 4B-C). All peptides, excluding the negative control DRx-097A-R, induced a dose-dependent inhibition of MDM2-mediated p53 ubiquitination (relative IC50s = 0.14 - 0.19 pM) indicative of on-target inhibition of MDM2 E3-ligase activity.

[1126] Peptides were then assessed at equimolar concentrations [3 pM] in a cancer cell viability assay, where their anti-proliferative capabilities were compared against a known MDM2 amplified TP53 wild-type viability), DRx-097A-R, DRx-097-S and DRx-097C had little or no anti-proliferative activity. However, DRx-097-R, DRx-097D-R, DRx-098-R, DRx-098D-R and DRx-097C-R all markedly inhibited U2-OS cell proliferation. These data indicate that anti-proliferative activity observed is not a random effect of the peptides (i.e., DRx-097A-R had no effect). Findings also suggest that D-R9 may represent a superior approach to enhancing cell-penetrating capability than stearic acid, as seen when comparing the activity of DRx-097-S versus that of DRx-097-R. Further, head-to-tail cyclisation of DRx-097 (i.e., DRx-097C) did not enable the peptide to cross the cell membrane. Improved anti-proliferative activity of DRx-097C-R suggests the difference in activity vs. DRx-097C is driven by D-R9, enhanced cell-penetrating capability. Interestingly, DRx-097-R / 097D-R / 098-R / 098D-R / 097C-R induced a more pronounced anti-proliferative effect than Idasanutlin, a clinical candidate positive MDM2 inhibitor control. Idasanutlin functions via a different mechanism, disrupting the MDM2 - p53 protein-protein interaction. Therefore, it could be suggested that U2-OS are more sensitive to MDM2 dimerisation inhibition than MDM2-p53 inhibition.

[1127] To confirm the anti-proliferative activity induced by DRx-098D-R is associated with its ability to disrupt MDM2 dimerisation, HA-MDM2 (435-C) and Myc-MDMX (428-C) overexpressing U2-OS cell models were generated (Figure 6A-B). Compared to vehicle [0.25% DMSO, 4 Hrs] and DRx-097A-R [5 pM, 4 Hrs], DRx-098D-R [0.5 or 5 pM, 4 Hrs] treated Myc-MDMX (428-C) overexpressing U2-OS cells expressed significantly lower levels of the Myc-MDMX (428-C) - MDM2 (full-length, endogenous) protein complex (Figure 7). This was also true in a HA-MDM2 (435-C) overexpressing U2-OS cell model (Figure 8). Data indicates DRx-098D-R’s ability to cross the cell-membrane and downregulate MDM2 homodimerisation and heterodimerisation.

[1128] Having confirmed DRx-098D-R’s anti-proliferative activity is a consequence of its ability to directly bind MDM2 and MDMX, inhibit MDM2 E3-ligase activity, and disrupt MDM2 homodimerisation and heterodimerisation, its therapeutic utility was further evaluated in another well-studied MDM2 / MDMX- dependent cancer cell line - HCT116 (human colorectal cancer). Utilising a real-time cellular analysis platform (xCELLigence), DRx-098D-R's anti-proliferative activity and duration of response was assessed (Figure 9). Growth inhibition was observed at [1 pM] and [5 pM], but not [0.1 pM]. At [5 pM], growth inhibition persisted for the duration of the experiment (48 Hrs). However, [1 pM] DRx-098D-R antiproliferative activity did not completely halt HCT116 cell growth, suggesting a higher concentration is 008849002

[1129] 97 required if cancer cell growth is to be abolished. This hypothesis was confirmed in an endpoint CellTiter Gio cell viability assay, where DRx-098D-R demonstrated a growth IC50 of [2.26 pM] vs. HCT116 cells (Figure 10A). Importantly, non-cancerous human cell lines HEK293 (human kidney epithelial) and IMR-90 (human lung fibroblast) treated with equimolar concentrations of DRx-098D-R [1 , 3 and 5 pM] resulted in no significant reduction in cell viability - indicative of a cancer cell specific effect (Figure 10B).

[1130] As anticipated (based on our current understanding of MDM2 / MDMX biology), HCT116 cells treated with equimolar concentrations of DRx-098D-R or Idasanutlin (but not DRx-097A-R or vehicle) upregulated pro- apoptotic protein markers including cleaved PARP (Figure 11 A, Top), cleaved caspase 3 (Figure 11 A, Bottom) and Annexin V binding (Figure 11 B). In line with existing MDM2 inhibitors, disrupting MDM2 dimerisation DRx-098D-R (but not vehicle or DRx-097A-R) significantly upregulated p21 , p53 and MDM2 protein expression (not MDMX) in HCT116 cells (Figure 12). Significant upregulation of p53 protein expression was shown to persist 24 Hrs after DRx-098D-R wash-out (Figure 13). These findings indicated that DRx-098D-R mediated disruption of MDM2 dimerisation acts (at least in part) through known MDM2 / MDMX mechanisms underpinning TP53 wild-type cancer cell survival.

[1131] In the presence of TP53 mutation(s), MDM2 and MDMX remain pro-oncogenic; but in a p53-independent manner. To determine if MDM2 dimerisation disruption elicits anti-proliferative activity in this context, HCT116 p53 knockout cells were treated with DRx-098D-R. Significantly, anti-proliferative activity was observed with a relative growth IC50 similar to that of HCT116 p53 wild-type [3.85 pM] (Figure 14A). This anti-proliferative activity was not observed with DRx-097A-R or vehicle. Crucially, Idasanutlin had no antiproliferative activity, confirming previous findings highlighting that targeting p53-dependent MDM2 signalling (i.e., via disruption of MDM2-p53) is a redundant therapeutic strategy [15,16] (Figure 14B). Endogenous protein expression of MDM2 and MDMX were detected in HCT116 p53 knockout cells (Figure 14C). These findings demonstrate that DRx-098D-R mediated MDM2 dimerisation disruption is a potentially viable and superior approach to inhibiting MDM2 / MDMX cancer cell growth, independent of p53. These findings were recapitulated in two human acute myeloid leukaemia (AML) cell lines, where DRx-098D-R inhibited the growth of THP-1 (TP53 mutant, [GIC50 - 2.22 pM]) and MOLM-13 (TP53 wildtype, [GIC50 - 2.27 pM]), irrespective of TP53 mutational status (Figure 15). As with HCT116 (Figure 11), DRx-098D-R (but not Idasanutlin) significantly upregulated pro-apoptotic annexin V binding in the THP-1 TP53 mutant cell line.

[1132] To further determine DRx-098D-R’s ability to inhibit cancer cell growth, independent of TP53 mutational status, a small panel of human cancer cell lines from a broad range of lineages were assessed (Figure 17). In all cell lines, except PANC1 , DRx-098D-R inhibited cancer cell growth with similar potency [GIC50 = 2.67 - 3.93 pM]. When comparing anti-proliferative activity of DRx-098D-R and Idasanutlin [3 pM] against all cell lines, DRx-098D-R was significantly more potent (Figure 18). Data adds evidence that disruption of MDM2 dimerisation is a superior therapeutic approach to treating TP53 mutant cancers vs. existing MDM2-p53 inhibitor approaches and continues to highlight a role for MDM2 / MDMX-dependency in cancer, independent of p53. Interestingly, all cell lines (except PANC1) expressed non-significantly different levels of combined MDM2 / MDMX protein expression (Figure 19). This was not true for PANC1 , 008849002

[1133] 98 which expressed significantly lower levels. Given that PANC1 is the only cell line in the panel to not respond to DRx-098D-R, it can be hypothesised that DRx-098D-R sensitivity is directly associated with the relative protein load of MDM2 and MDMX (and therefore MDM2 dimerisation).

[1134] Following on from the successful demonstration of DRx-098D-R’s ability to bind MDM2 and MDMX, disrupt both homo- and hetero-dimerisation, inhibit MDM2 E3-ligase activity, and inhibit cancer cell growth (independent of TP53 mutational status) through a pro-apoptotic mechanism, we sought to further develop DRx-098D-R’s structural characteristics. Firstly, a linker was introduced between the cellpenetrating peptide and the core disruptor peptide, enabling an added degree of separation and flexibility between these two peptide entities. Secondly, removal of the central methionine (Met484) was investigated, aimed at avoiding oxidation of this residue. Thirdly, to increase potential for the peptide to be resistant to proteolytic degradation, additional non-native amino acids were introduced at R479 / Met484 (considered non-essential for interactions with MDM2 / MDMX). Fourthly, conjugation of a C20 diacid o the core disruptor peptide was facilitated through linkage (via a ethylenediamine linker) to the side chain of a glutamic acid residue (substituted in place of native Val486, another non-essential amino acid), another strategy aimed at improving resistance to proteolytic degradation / enhancing circulating half-life of the peptide. Finally, as other studies have shown little or no difference in cell-penetrating capabilities of octaarginine vs. nona-arginine, we incorporated the shorter octa-D-arginine (D-R8) instead of the previously utilised D-R9. This has the potential to reduce manufacturing costs whilst maintaining cell-penetrating activity.

[1135] To compare the anti-proliferative activity of the various peptides , A549 cells were treated with a 6-point dose response of each peptide [0.1 - 10 pM] for 48 Hrs (Figure 20). Compared to DRx-098D-R, DRx-990, DRx-991 and DRx-992 induced a non-significantly different anti-proliferative response [GIC50 = 3.2 - 4.22 pM]. DRx-993 and DRx-994 however were significantly less potent (>5 fold higher GIC50 [22.86 - 30.63 pM]). This indicates that substituting Val486 with Glu and the subsequent conjugation of a C20 diacid at that location within the core disruptor peptide negatively impacts its activity. Therefore, these specific modifications are not considered viable options going forward. Neither negative control peptides DRx-097A-R or DRx-992-C inhibited A549 cancer cell growth (Figure 20C).

[1136] Peptide library was then assessed (excluding DRx-993 / DRx-993) in a real-time cellular growth assay (xCELLigence), where A459 cancer cell growth was monitored over a 72 Hr period following [5 pM] treatment with each peptide (Figure 21). Compared to vehicle and respective negative control peptides, DRx-098D-R, DRx-990, DRx-991 and DRx-992 all significantly inhibited cancer cell growth (% A549 growth inhibition at 72 Hrs = 58.5% - 86.8%). Of all the peptides, DRx-992 inhibited A549 cells the most, suggesting it is the most anti-proliferative of the peptides tested. Though DRx-098D-R demonstrated equipotency in the 48 Hr (2% FBS, low serum) end-point viability assay vs. DRx-992 (Figure 20), the superior response of DRx-992 in the 72 Hr (10% FBS, high serum) real-time growth assay may reflect relative serum protein binding (not directly tested) and / or duration of response (i.e., DRx-992 possesses longer lasting activity vs. DRx-098D-R). 008849002

[1137] 99

[1138] To confirm that anti-proliferative activity observed in Figures 20-21 is a result of on-target activity, DRx-

[1139] 991 and DRx-992 MDM2 dimerisation disruption ability was assessed against endogenous MDM2:MDMX heterodimerisation in A549 cells (Figure 22). As expected, DRx-098D-R (positive control) abolished heterodimerisation. This was also true for DRx-991 and DRx-992, but not respective negative control peptides (DRx-097A-R or DRx-992-C) or vehicle. Interestingly, Idasanutlin (an MDM2 - p53 disruptor) did not significantly inhibit MDM2 dimerisation, providing further evidence of a differentiated mechanism of action. In line with data presented in Figures 12-13, DRx-992 (but not DRx-992-C) upregulated MDM2 / p53 / p21 protein expression in A549 cells - providing further evidence of on-target mechanism (Figure 23).

[1140] To confirm DRx-992’s ability to inhibit the growth of human cancer cell lines harbouring a TP53 mutation, DRx-992 was compared with Idasanutlin against a panel of TP53 mutant AML cell lines (Figure 24). In all cases, excluding THP-1, DRx-992 was more potent than Idasanutlin. THP-1 cells have an increased dependency on p73, which in the case of TP53 mutations can often be upregulated. As p73 binds MDM2 at the same location as p53, Idasanutlin is also capable of inhibiting this interaction - making the antiproliferative activity observed a likely consequence of this mechanism. Nonetheless, DRx-992 is significantly more potent than Idasanutlin, further supporting this differentiated mechanism of action as being a superior approach to inhibiting MDM2 in the presence of TP53 mutations. DRx-992 again demonstrated this same outcome in a TP53 mutant human neuroblastoma cell line (SK-N-Be(2)), where the pro-apoptotic / anti-proliferative actions of DRx-992 were not observed with Idasanutlin (Figure 25).

[1141] Further confirmation was obtained via a different end-point cell viability assay (Cell-Titer Gio), where DRx-

[1142] 992 (Figure 27A) and Idasanutlin (Figure 27B) were tested against a larger panel of TP53 mutant human neuroblastoma cell lines including SK-N-Be(2) (homozygous TP53 mutant), SK-N-FI (homozygous TP53 mutant), NGP (heterozygous TP53 mutant), N_N20R1 (heterozygous TP53 mutant, NGP derived, MDM2- p53 inhibitor [Nutlin-3a] resistant) and N_M5R1 (heterozygous TP53 mutant, NGP derived, MDM2-p53 inhibitor [MI-63] resistant) (19). Of significance, observed anti-cancer activity of DRx-992 vs. NGP is not negatively impacted when the cell line artificially acquires resistance to either MDM2-p53 small molecule inhibitor (nutlin 3a or MI-63) (Figure 27 A, C). This is not true for Idasanutlin, where resistance to Idasanutlin is observed in both N_N20R1 and N_M5R1 (Figure 27B-C).

[1143] To further characterise the mechanism of action of DRx-992, c-MYC amplified HL-60 cells were treated for 6 and 24 hrs with DRx-992-C or DRx-992 [3 pM] and RNA sequencing was performed. At both timepoints, DRx-992 strongly reduced c-MYC mRNA (Figure 28A) and protein (Figure 28B) levels. This was confirmed in a MYCN amplified cell line (SK-N-Be(2)) at the protein level (Figure. 28C).

[1144] Deeper evaluation of DRx-992-mediated MDM2 dimer disruption was assessed in c-MYC amplified HL-60 cells, where DRx-992, but not DRx-992-C, induced a large transcriptomic response at both 6 and 24 hrs timepoints, with the largest change observed following 6 hrs treatment (1 ,379 upregulated and 901 downregulated genes) (Figure 29A). Gene set enrichment analysis (GSEA) of significantly upregulated genes highlights enrichment for pathways associated with myeloid differentiation, granulocyte functions, 008849002

[1145] 100 inflammatory activation, and apoptosis (Figure 29B) which suggests the peptide may promote granulocytic differentiation of HL-60 cells.

[1146] Notably, RNA-seq results indicate that DRx-992 upregulates CD11b (ITGAM) mRNA expression, a well- established marker of myeloid differentiation (Figure 30A). To confirm DRx-992’s ability to promote differentiation, HL-60 were treated for up to 72 hrs and assessed for cell surface expression of granulocytic / monocytic (CD11b) and monocytic (CD14) markers. DRx-992 [3 pM] increased the expression of CD11b (Figure 30B) but had no effect on CD14 expression (Figure 30C), indicating the MDM2 dimer disruption induces granulocytic differentiation. RNA-seq data further supports these findings, with significantly reduced expression of myeloperoxidase (MPO), proteinase 3 (PRTN3), and cathepsin G (CSTG) - key components of primary azurophilic granules that are normally diminished during myeloid maturation (Figure 30D). Consistent with this, DRx-992-treated cells exhibit a reduced nuclearcytoplasmic ratio, segmented nuclei, and lighter cytoplasmic staining, resembling a more mature granulocyte / neutrophil morphology (Figure 30E).

[1147] Differentiation-inducing agents (such as all-trans retinoic acid [ATRA] and arsenic trioxide [ATO]) have been successfully used for certain AML subtypes such as acute promyelocytic leukaemia (APL), however, a small subset of patients are refractory or relapse following ATRA / ATO treatment (20). In addition, despite the limited clinical utility of differentiation-inducing drugs in non-APL AML thus far, differentiation therapy remains an attractive strategy to treat AML more broadly (21-23). As a result, combined use of targeted therapeutics with ATRA has been explored to both address ATRA / ATO resistance in APL (24) and enhance ATRA response rates in non-APL AML (25-28). In fact, MDM2 has been reported to promote cancer sternness and suppress osteoblast differentiation independent of p53 (29), with MDM2 E3 ligase inhibition synergising with ATRA to induce differentiation of osteosarcoma cells (30). In line with this, MDM2 dimer disruption (via DRx-992) was shown to potentiate ATRA- mediated CD11b induction in both HL-60 (APL) and MOLM-13 (non-APL) cells (Figure 30F).

[1148] Although the success of differentiation inducing agents (e.g. retinoic acid derivatives (ATRA, 13-cis RA, 9- cis RA), ATO, cAMP, sodium butyrate, and cytokines) in treating APL have been attributed to its uncommon genetic simplicity of predominantly a single oncogenic driver (PML-RARa), differentiation therapies also demonstrate potential in heterogenous cancers characterised by a differentiation block (31 ). This includes neuroblastoma (NB), with 13-cis RA (isotretinoin) clinically utilised for high-risk NB and significant research interest in adopting combinations with targeted therapeutics to potentiate its prodifferentiating actions and hinder resistance (32). Paediatric high-grade gliomas are another aggressive and genetically diverse tumour that may be therapeutically susceptible to induced neuronal differentiation (33). Given the negative regulatory effect exerted by targeted MDM2 dimer disruption on c-MYC / MYCN, its therapeutic utility may extend to cancers whereby c-MYC / MYCN signalling is important in maintaining their undifferentiated state, including neuroblastoma, poorly differentiated colorectal cancer and hepatocellular carcinoma, neuroendocrine prostate cancer, rhabdomyosarcoma, and glioma (34). Solid tumours pathologically classified as undifferentiated or poorly differentiated are often highly aggressive and treatment insensitive (35). Utilising differentiation-inducing drugs (such as an MDM2 dimer disruptor), 008849002

[1149] 101 as monotherapy or combination therapy, to transcriptionally reprogramme and revert malignant cancer phenotypes to more differentiated states may offer a potential strategy to render tumours less aggressive and more manageable to combine with conventional therapeutic approaches (36).

[1150] Prior to further optimisation of DRx-992’s structure, activity was compared against known published MDMX-derived disruptor peptides of MDM2:MDMX heterodimerisation (Pep-3 and Pep-9) (19). As these peptides are not naturally cell-permeable, an N-terminal D-octa-arginine cell-penetrating peptide was incorporated into Pep-3 and Pep-9, creating MDMX-3R and MDMX-9R, respectively. At equimolar concentrations (5 uM), DRx-992, but not DRx-992-C, MDMX-3R or MDMX-9R markedly inhibited TP53 mutant SK-N-Be(2) cancer cell growth (Figure 31). Findings suggest, even though Pep-3 and Pep-9 have demonstrated anti-cancer activity against TP53 wild-type cancer cell lines, that these MDMX-derived disruptors do not translate this activity in the context of a TP53 mutant cell line.

[1151] Aimed at improving the relative potency (and solubility) of DRx-992, several modifications associated with the (i) cell-penetrating moeity, (ii) solubility and (iii) structural ridigity of DRx-992 were evaluated (Figure 32; compounds 2721 , 3211 , 7175, 7176, 1723, 1724, 1797, 1211 , 3276, 3277 and 3275). To test the impact of these modifications, peptides anti-proliferative activity were tested over a prolonged 5-day (120 hrs) treatment period against TP53 mutant SK-N-Be(2) cells (Figure 32D).

[1152] Firstly, removal of DRx-992’s cell-penetrating D-octa-arginine peptide (i.e., 2721) or replacement with palmitic acid (i.e., 3211) abolished anti-proliferative activity vs. DRx-992 (Figure. 32D). Replacing D-octa- arginine with the cyclic L-arginine - C12 short chain fatty acid (C12-Cyclic CPP) integrated cellpenetrating moeity enabled equal activity vs. DRx-992 in the case of 7175, but not 7176. 7176 utilised a disulphide conjugation approach between disrutor peptide and cell-penetrating peptide, as opposed to a non-cleavable thio-ether linker (same as DRx-992) with 7175, indicating disulphide linkage is less favourable (Figure 32). Progressing with the C12-Cyclic CPP (considered to be more stable than polyarginines, and noticably improving solubility of peptide upon observation), substitution of non- contact / key residues isoleucine (position 4) and / or valine (position 8) with glutamine I aspartic acid was assessed, aimed at further improving solubility (1723, 1724, 1797). However, in all cases, activity was markedly reduced making these modifications non-viable (Figure 32D). Finally, backbone modifications at the same non-contact / key residues was evaluated. Incorporation of Aib-Aib (1211) and homocysteine (3276; i, i+4) enabled similar activity vs. 7175 / DRx-992, whilst cysteine (3275; i, i+4) reduced activity. However, it was found that cyclisation with triazole (3277; I , i+4) significantly enhanced anti-proliferative activity >2-fold (Figure 32D, Figure 33A-B). As anticipated, neither sulanemadlin (peptide disruptor of both MDM2-p53 and MDMX-p53) or Idasanutlin (small molecule disruptor of MDM2-p53) inhibited SK-N- Be(2) growth. L-octa-arginine and DRx-992 (cell-penetrating knockout negative control peptide) also had no negative impact on cell viability, indicating anti-proliferative activity is being specifically induced by disruptor peptide activity.

[1153] Conclusion 008849002

[1154] 102

[1155] The peptides described represent next-generation MDM2 / MDMX inhibitors, capable of exploiting MDM2 / MDMX activity independent of p53 mutational status of the target cells. We anticipate this differentiated approach to have therapeutic utility in all MDM2 / MDMX-dependent cancers, irrespective of lineage (solid or haematological) or TP53 mutational status.

[1156] 008849002

[1157] 103

[1158] References

[1159] A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. The entirety of each of these references is incorporated herein.

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[1164] 5. Kung, CP and Weber, JD. It's Getting Complicated-A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy. Front Cell Dev Biol. 10: 818744 (2022).

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[1167] 8. Linares, L.K., Hengstermann, A., Ciechanover, A., Muller, S. and Scheffner, M. HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. PNAS. 100(21): 12009-12014 (2003).

[1168] 9. Kawai, H., Lopez- Pajares, V., Kim, M.M., Wiederschain, D. and Yuan, Z.M. RING Domain- Mediated Interaction Is a Requirement for MDM2’s E3 Ligase Activity. Cancer Res. 67(13): 6026- 6030 (2007).

[1169] 10. Nomura, K., Klejnot, M., Kowalczyk, D., Hock, A.K., et al. Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity. 24(7): 578-587 (2017).

[1170] 11. Egorova, O., Lau, H.H., McGraphery, K. and Sheng, Y. Mdm2 and MdmX RING Domains Play Distinct Roles in the Regulation of p53 Responses: A Comparative Study of Mdm2 and MdmX RING Domains in U2OS Cells. Int J Mol Sci. 21(4): 1309 (2020).

[1171] 12. Klein, A.M., Biderman, L., Tong, D., Alaghebandan, B., et al. MDM2, MDMX, and p73 regulate cellcycle progression in the absence of wild-type p53. PNAS. 118(44): e2102420118 (2021 ).

[1172] 13. Amartely, H., Losub-Amir, Anat. and Friedler, Assaf. Identifying protein-protein interactions sites using peptide arrays. Journal of Visualized Experiments. (93):52097 (2014).

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[1174] 15. Lakoma, A., Barbieri, E., Agarwal, S., Jackson, J., et al. The MDM2 small-molecule inhibitor RG7388 leads to potent tumor inhibition in p53 wild-type neuroblastoma. Cell Death Discov. 1 : 15026 (2015).

[1175] 16. Humpton, T.J., Hock, A.K., Maddocks, O.D.K. and Vousden, K.H. p53-mediated adaptation to serine starvation is retained by a common tumour-derived mutant. Cancer Metab. 6:18 (2018) 008849002

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[1179] 19. Drummond, C.J. et al. TP53 mutant MDM2-amplified cell lines selected for resistance to MDM2- p53 binding antagonists retain sensitivity to ionizing radiation. Oncotarget. 7(29): 46203-46218 (2016)

[1180] 20. Iyer, et al. The treatment of acute promyelocytic leukemia in 2023: Paradigm, advances, and future directions. Front Oncol. 12: 1062524 (2023)

[1181] 21. Yankova, et al. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature. 593(7860): 597-601 (2021)

[1182] 22. Jose-Eneriz, et al. Epigenetic-based differentiation therapy for Acute Myeloid Leukemia. Nat Commun. 15(1 ): 5570 (2024)

[1183] 23. Hosseini, et al. Perturbing LSD1 and WNT rewires transcription to synergistically induce AML differentiation. Nature. 642(8067): 508-518 (2025)

[1184] 24. Dai, et al. Targeting HDAC3 to overcome the resistance to ATRA or arsenic in acute promyelocytic leukemia through ubiquitination and degradation of PML-RARa. Cell Death & Differentiation. 30, 1320-1333 (2023)

[1185] 25. Schenk, et al. Inhibition of the LSD1 (KDM1 A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nature Medicine. 18, 605-611 (2012)

[1186] 26. Skopek, et al. Synergistic potential of CDK4 / 6 inhibitors and ATRA in non-APL AML. British Journal of Haematology. 00: 1-10 (2025)

[1187] 27. Baba, et al. Enlarged PML-nuclear bodies trigger conflicting cell cycle signal-mediated cytotoxicity in leukemia cells. Cell Death & Disease. 16, 586 (2025)

[1188] 28. Magliulo, et al. The transcription factor HIF2a partakes in the differentiation block of acute myeloid leukemia. EMBO Molecular Medicine. 15: e17810 (2023)

[1189] 29. Wienken, et al. MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Sternness- Promoting Chromatin Modifications Independent of p53. Molecular Cell. 61(1) 68-83 (2016)

[1190] 30. Ying, et al. The E3 ubiquitin protein ligase MDM2 dictates all-trans retinoic acid-induced osteoblastic differentiation of osteosarcoma cells by modulating the degradation of RARa. Oncogene. 35(33): 4358-4367 (2016)

[1191] 31. de The. Differentiation therapy revisited. Nature Reviews Cancer. 18, 117-127 (2018)

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[1200] 106

[1201] Numbered paragraphs:

[1202] 1. A MDM2 inhibitor comprising a disruptor component P which is capable of inhibiting MDM2:MDM2 homodimerisation and / or MDM2:MDMX heterodimerisation, wherein said disruptor component P is a peptide of at least 12 and no more than 20 residues in length, comprising

[1203] (i) a core sequence

[1204] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1 ) or an all-D or retro-inverso form thereof;

[1205] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2) or a retro-inverso form thereof;

[1206] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3) or a retro-inverso- form thereof;

[1207] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[1208] (iii) a peptoid or N-methyl version of (i) or (ii).

[1209] 2. A MDM2 inhibitor according to paragraph 1 , wherein P comprises:

[1210] Arg or D-Arg at position 1 , or an N-methyl or N-substituted glycine analogue thereof;

[1211] Tyr, Trp, Phe, Leu, He or Vai at position 11 , or a D-form, N-methyl or N-substituted glycine analogue thereof; and / or

[1212] Phe, Trp, Tyr, Leu, He or Vai at position 12, or a D-form, N-methyl or N-substituted glycine analogue thereof. 008849002

[1213] 107

[1214] 3. A MDM2 inhibitor according to paragraph 1 or paragraph 2, wherein P comprises all three of:

[1215] Arg or D-Arg at position 1 , or an N-methyl or N-substituted glycine analogue thereof;

[1216] Tyr, Trp, Phe, Leu, He or Vai at position 11 , or a D-form, N-methyl or N-substituted glycine analogue thereof; and

[1217] Phe, Trp, Tyr, Leu, He or Vai at position 12, or a D-form, N-methyl or N-substituted glycine analogue thereof.

[1218] 4. A MDM2 inhibitor according to any one of paragraphs 1 to 3, wherein the residues at positions 4 and 7 or at positions 4 and 8 are a pair of residues <D and whose side chains participate in a covalent bond.

[1219] 5. A MDM2 inhibitor according to any one of the preceding paragraphs, further comprising one or more heterologous moieties.

[1220] 6. A MDM2 inhibitor according to paragraph 5, wherein the heterologous moiety is linked to a side chain of P at a residue , or to a N-terminal or C-terminal functional group.

[1221] 7. A MDM2 inhibitor according to paragraph 5 or paragraph 6, wherein the heterologous moiety is a membrane transit moiety.

[1222] 8. A MDM2 inhibitor according to paragraph 7, wherein the membrane transit moiety is a cell penetrating peptide.

[1223] 9. A MDM2 inhibitor according to paragraph 8, wherein the cell penetrating peptide forms a fusion protein with P, e.g. wherein the cell penetrating peptide is located N-terminal of the core sequence and is optionally spaced from the N-terminus of the core sequence by a linker peptide.

[1224] 10. An MDM2 inhibitor according to paragraph 8 or paragraph 9, wherein the cell penetrating peptide is poly-arginine, poly-D-arginine, GRKKRRQRRR, Grkkrrqrrr, cyclo[GRKKRRQRRR] or cyclo[Grkkrrqrrr], e.g._Arg4-io or [D-Arg]4-io, e.g. Args, Args, [D-Arg]s or [D-Arg]s. 008849002

[1225] 108

[1226] 11. A MDM2 inhibitor according to any one of the preceding paragraphs, wherein the core sequence has the formula:

[1227] X1 -X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12 wherein

[1228] XI is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[1229] X2 is selected from Gin, Phe, Tyr, Leu, He, Gly, Met, Cys, His, Thr, Pro, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[1230] X3 is selected from Pro, Gly, Cys, His, Thr, Gin, Asn and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or a residue

[1231] X4 is selected from He, Trp, Phe, Tyr, Leu, Vai, Gly, Met, Cys, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof, or is a residue <D or ;

[1232] X5 is selected from Gin, Trp, Phe, Leu, lie, Vai, Met, His, Thr, Pro, Ser and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[1233] X6 is selected from Met, Tyr, Leu, lie, Vai, Gly, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N- substituted glycine analogue thereof;

[1234] X7 is selected from lie, Phe, Tyr, Leu, Vai, Met, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ^P;

[1235] X8 is selected from Vai, Trp, Phe, Tyr, Leu, lie, Gly, Met, Cys, His, Thr, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue 4^;

[1236] X9 is selected from Leu, Trp, Phe, Tyr, lie, Vai, Gly, Met, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[1237] X10 is selected from Thr, Phe, Leu, lie, Vai, Gly, Met, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[1238] XI I is selected from Tyr, Trp, Phe, Leu, lie, Vai, Gly, Met, Cys, His, Thr, Pro, Gin, Asn, Ser, Glu, Arg and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[1239] X12 is selected from Phe, Trp, Tyr, Leu, lie, Vai, Gly, Met, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue * and vice versa, a maximum of one residue ^P is present, and, when present, the side chains of residues and 'P form a covalent bond; 008849002

[1240] 109 where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[1241] (i)

[1242] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1 ) or an all-D form thereof;

[1243] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[1244] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[1245] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[1246] (iii) a peptoid, N-methyl or retro-inverso version of (i) or (ii).

[1247] 12. A MDM2 inhibitor according to paragraph 11 , wherein:

[1248] X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[1249] X2 is selected from Gin, Phe, Tyr, Leu, He, Gly, Met, Cys, His, Thr, Pro, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[1250] X3 is selected from Pro, Gly, Cys, His, Thr, Gin, Asn and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[1251] X4 is selected from He, Trp, Phe, Tyr, Leu, Vai, Gly, Met, Cys, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof, or is a residue <D or

[1252] X5 is selected from Gin, Trp, Phe, Leu, lie, Vai, Met, His, Thr, Pro, Ser and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[1253] X6 is selected from Met, Tyr, Leu, lie, Vai, Gly, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N- substituted glycine analogue thereof; 008849002

[1254] 110

[1255] X7 is selected from He, Phe, Tyr, Leu, Vai, Met, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue 4*;

[1256] X8 is selected from Vai, Trp, Phe, Tyr, Leu, He, Gly, Met, Cys, His, Thr, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue *;

[1257] X9 is selected from Leu, Trp, Phe, Tyr, lie, Vai, Gly, Met, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[1258] X10 is selected from Thr, Phe, Leu, lie, Vai, Gly, Met, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[1259] X11 is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;

[1260] X12 is selected from Phe, Trp, Tyr, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue 4^ and vice versa, a maximum of one residue 41is present, and, when present, the side chains of residues <D and 4* form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[1261] (i)

[1262] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;

[1263] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[1264] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[1265] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[1266] (iii) a peptoid, N-methyl or retro-inverso version of (i) or (ii). 008849002

[1267] 111

[1268] 13. A MDM2 inhibitor according to paragraph 11 or paragraph 12, wherein:

[1269] XI is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[1270] X2 is selected from Gin, Gly, His, Thr, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[1271] X3 is selected from Pro, Gly and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[1272] X4 is selected from He, Trp, Tyr, Leu, Vai, Gly, His, Thr, Gin and Ser, or a D-form, N-methyl, or N- substituted glycine analogue thereof, or is a residue <P or ;

[1273] X5 is selected from Gin, His, Thr and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[1274] X6 is selected from Met, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[1275] X7 is selected from He, Phe, Tyr, Leu, Vai, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue1;

[1276] X8 is selected from Vai, Phe, Tyr, Leu, lie, Thr, Asn, Ser, Asp and Glu, or a D-form, N-methyl, or N- substituted glycine analogue thereof, or is a residue1;

[1277] X9 is selected from Leu, Phe, Tyr, lie, Vai, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue (;

[1278] X10 is selected from Thr, Gly, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[1279] XI I is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;

[1280] X12 is selected from Phe, Trp, Tyr, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue and vice versa, a maximum of one residue is present, and, when present, the side chains of residues <D and form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is: 008849002

[1281] 112

[1282] (i)

[1283] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;

[1284] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[1285] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[1286] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[1287] (iii) a peptoid, N-methyl version or retro-inverso form of (i) or (ii).

[1288] 14. A MDM2 inhibitor according to any one of paragraphs 11 to 13, wherein:

[1289] X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;

[1290] X2 is selected from Gin, Gly, His, Thr, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue

[1291] X3 is selected from Pro, Gly and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;

[1292] X4 is selected from He, Gly, His, Thr, Gin and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue or

[1293] X5 is selected from Gin, His, Thr and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[1294] X6 is selected from Met, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[1295] X7 is selected from He, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue MJ;

[1296] X8 is selected from Vai, Thr, Asn, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue MJ;

[1297] X9 is selected from Leu, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ; 008849002

[1298] 113

[1299] X10 is selected from Thr, Gly, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;

[1300] X11 is selected from Tyr, Trp, Phe, Leu, He and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;

[1301] X12 is selected from Phe, Trp, Tyr, Leu, He and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue * and vice versa, a maximum of one residue 41is present, and, when present, the side chains of residues 0 and MJ form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:

[1302] (i)

[1303] (a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;

[1304] (b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[1305] (c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);

[1306] (ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or

[1307] (iii) a peptoid, N-methyl version or retro-inverso form of (i) or (ii).

[1308] 15. A MDM2 inhibitor according to any one of paragraphs 11 to 14, wherein the core sequence has the formula:

[1309] X1-Gln-Pro-X4-Gln-X6-X7-X8-X9-Thr-X11-X12 where 008849002

[1310] 114

[1311] X1 is selected from Arg and D-Arg

[1312] X4 is He, or is a residue

[1313] X6 is selected from Met and Thr, or a D-form thereof;

[1314] X7 is He, or is a residue

[1315] X8 is Vai, or is a residue MJ;

[1316] X9 is Leu, or is a residue £

[1317] X11 is selected from Tyr and Leu, or a D-form thereof;

[1318] X12 is selected from Phe and D-Phe

[1319] 16. A MDM2 inhibitor according to any one of the preceding paragraphs, wherein the core sequence comprises a sequence selected from:

[1320] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1);

[1321] Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);

[1322] [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; and

[1323] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe; or a peptoid, N-methyl or retro-inverso version thereof.

[1324] 17. A MDM2 inhibitor according to any one of paragraphs 1 to 15, wherein the core sequence comprises a sequence selected from:

[1325] Arg-GIn-Pro-cD-GIn-Met-lle-^P-Leu-Thr-Leu-Phe;

[1326] Arg-GIn-Pro-cD-GIn-Met-lle-^-Leu-Thr-tD-LeuHD-Phe];

[1327] [D-Arg]-Gln-Pro-0-Gln-[D-Thr]-lle-'4J-Leu-Thr-[D-Leu]-[D-Phe];

[1328] Arg-GIn-Pro-cD-GIn-Met-lle-^P-Leu-Thr-Tyr-Phe;

[1329] Arg-GIn-Pro-O-GIn-Met-'+’-Val-Leu-Thr-Leu-Phe;

[1330] Arg-Gln-Pro-(U-Gln-Met-4’-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1331] [D-Arg]-Gln-Pro-(D-Gln-[D-Thr]-iP-Val-Leu-Thr-[D-Leu]-[D-Phe]; and

[1332] Arg-GIn-Pro-O-GIn-Met-'+’-Val-Leu-Thr-Tyr-Phe; where the side chains of residues <t> and form a covalent bond; or a peptoid, N-methyl or retro-inverso version thereof. 008849002

[1333] 115

[1334] 18. A MDM2 inhibitor according to any one of paragraphs 1 to 15, wherein the disruptor component P comprises a sequence selected from:

[1335] ^-Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe;

[1336] £-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1337] <-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1338] ^-Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe;

[1339] Arg-GIn-Pro-lle-GIn-Met-lle-Val-^-Thr-Leu-Phe;

[1340] Arg-Gln-Pro-lle-Gln-Met-lle-Val-<-Thr-[D-Leu]-[D-Phe];

[1341] [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-<-Thr-[D-Leu]-[D-Phe]; and

[1342] Arg-GIn-Pro-lle-GIn-Met-lle-Val-^-Thr-Tyr-Phe; where the side chain of the residue ( forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof.

[1343] 19. A MDM2 inhibitor according to any one of paragraphs 1 to 15, wherein the disruptor component P comprises a sequence selected from:

[1344] (-Arg-GIn-Pro-cb-GIn-Met-lle-^P-Leu-Thr-Leu-Phe;

[1345] <-Arg-Gln-Pro-ct>-Gln-Met-lle-^-Leu-Thr-[D-Leu]-[D-Phe];

[1346] <-[D-Arg]-Gln-Pro-(P-Gln-[D-Thr]-lle-iP-Leu-Thr-[D-Leu]-[D-Phe];

[1347] (-Arg-GIn-Pro-cb-GIn-Met-lle-^P-Leu-Thr-Tyr-Phe;

[1348] (-Arg-GIn-Pro-cb-GIn-Met-^P-Val-Leu-Thr-Leu-Phe;

[1349] <-Arg-Gln-Pro-(D-Gln-Met-iP-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1350] <-[D-Arg]-Gln-Pro-(t>-Gln-[D-Thr]-'+,-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1351] ^-Arg-GIn-Pro-O-GIn-Met-MM / al-Leu-Thr-Tyr-Phe;

[1352] Arg-Gln-Pro-<D-Gln-Met-lle-'4J-(-Thr-Leu-Phe;

[1353] Arg-Gln-Pro-(U-Gln-Met-lle-'+,-<-Thr-[D-Leu]-[D-Phe];

[1354] [D-Arg]-Gln-Pro-(U-Gln-[D-Thr]-lle-'+,-<-Thr-[D-Leu]-[D-Phe]; 008849002

[1355] 116

[1356] Arg-GIn-Pro-O-GIn-Met-lle-'+'-^-Thr-Tyr-Phe;

[1357] Arg-GIn-Pro-O-GIn-Met-'+’-Val-^-Thr-Leu-Phe;

[1358] Arg-Gln-Pro-<P-Gln-Met-^-Val-<-Thr-[D-Leu]-[D-Phe];

[1359] [D-Arg]-Gln-Pro-O-Gln-[D-Thr]-^-Val <-Thr-[D-Leu]-[D-Phe]; and

[1360] Arg-GIn-Pro-O-GIn-Met-'+’-Val-^-Thr-Tyr-Phe; where the side chains of residues and 41form a covalent bond; and where the side chain of the residue ( forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof.

[1361] 20. A MDM2 inhibitor according to any one of the preceding paragraphs, having the formula

[1362] Z-L-P where

[1363] Z is a cell penetrating peptide;

[1364] P is the disruptor component; and

[1365] L is a linker peptide sequence (e.g. of 1-10 amino acids, e.g. of 1-5 amino acids), or represents a bond between Z and P; or a peptoid, N-methyl or retro-inverso version thereof.

[1366] 21 . A MDM2 inhibitor according to paragraph 20, having the formula

[1367] Y1 -Z-L-P- Y2 where

[1368] Y1 is H, Ac cr a heterologous moiety (e.g. H or Ac);

[1369] Z is a cell penetrating peptide;

[1370] P is the disruptor component;

[1371] L is a linker peptide sequence (e.g. of 1-10 amino acids, e.g. of 1-5 amino acids), or represents a bond between Z and P; and

[1372] Y2 is OH, NH2 or a heterologous moiety (e.g. OH or NH2). 008849002

[1373] 117

[1374] 22. A MDM2 inhibitor according to any one of the preceding paragraphs, comprising the sequence:

[1375] Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe;

[1376] (Stearoyl)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe;

[1377] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe;

[1378] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Tyr]-[D-Phe];

[1379] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Leu-Phe;

[1380] [D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1381] [D-Arg]8-Cys-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];

[1382] Cys(-Ac-[D-Arg]9-NH2)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; or

[1383] [D-Cys](-Ac-[D-Arg]9-NH2)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; or a peptoid, N-methyl or retro-inverso version thereof.

[1384] 23. A MDM2 inhibitor selected from:

[1385] Ac-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe-NH2;

[1386] (Stearoyl)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe-NH2 (DRx-97-S);

[1387] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe -NH2 (DRx-97-R);

[1388] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Tyr]-[D-Phe]-NH2 (DRx-97D-R);

[1389] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Leu-Phe-NH2 (DRx-98R);

[1390] Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2 (DRx-98D-R);

[1391] Ac-[D-Arg]8-Cys-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2 (DRx-990);

[1392] Ac-Cys(-Ac-[D-Arg]9-NH2)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2 (DRx-991 ); and

[1393] Ac-[D-Cys](-Ac-[D-Arg]9-NH2)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2 (DRx- 992); or a peptoid, N-methyl or retro-inverso version thereof.

[1394] 24. A MDM2 inhibitor according to any one of paragraphs 1 to 23 for use in the treatment of cancer, inflammatory disease, dementia or a neurodegenerative disease, nephropathy, or heart or cardiovascular disease. 008849002

[1395] 118

[1396] 25. A MDM2 inhibitor for use according to paragraph 24, wherein:

[1397] (a) the cancer is neuroblastoma, a myeloproliferative neoplasm (e.g. polycythemia vera or myelofibrosis), leukaemia (e.g. acute myeloid leukaemia,) lung cancer, colorectal cancer, osteosarcoma, melanoma or pancreatic cancer;

[1398] (b) the inflammatory disease is an autoimmune disease, e.g. rheumatoid arthritis, systemic lupus erythaematosus (SLE), pancreatitis or gastritis;

[1399] (c) the dementia or neurodegenerative disease is, or is associated with, for example, fragile X syndrome, Parkinson’s disease or Alzheimer’s disease; (d) the nephropathy is autosomal dominant polycystic kidney disease, renal fibrosis or diabetic nephropathy; or

[1400] (e) wherein the cardiovascular disease is myocardial infarction or atherosclerosis.

Claims

008849002119Claims:

1. A MDM2 inhibitor comprising a disruptor component P which is capable of inhibiting MDM2:MDM2 homodimerisation and / or MDM2:MDMX heterodimerisation, wherein said disruptor component P is a peptide of at least 12 and no more than 20 residues in length, comprising(i) a core sequence(a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1 ) or an all-D or retro-inverso form thereof;(b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2) or a retro-inverso form thereof;(c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3) or a retro-inverso- form thereof;(ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or(iii) a peptoid or N-methyl version of (i) or (ii).

2. A MDM2 inhibitor according to claim 1 , wherein P comprises:Arg or D-Arg at position 1 , or an N-methyl or N-substituted glycine analogue thereof;Tyr, Trp, Phe, Leu, He or Vai at position 11 , or a D-form, N-methyl or N-substituted glycine analogue thereof; and / orPhe, Trp, Tyr, Leu, He or Vai at position 12, or a D-form, N-methyl or N-substituted glycine analogue thereof.0088490021203. A MDM2 inhibitor according to claim 1 or claim 2, wherein P comprises all three of:Arg or D-Arg at position 1 , or an N-methyl or N-substituted glycine analogue thereof;Tyr, Trp, Phe, Leu, He or Vai at position 11 , or a D-form, N-methyl or N-substituted glycine analogue thereof; andPhe, Trp, Tyr, Leu, He or Vai at position 12, or a D-form, N-methyl or N-substituted glycine analogue thereof.

4. A MDM2 inhibitor according to any one of claims 1 to 3, wherein the residues at positions 4 and 7 or at positions 4 and 8 are a pair of residues and 4* whose side chains participate in a covalent bond.

5. A MDM2 inhibitor according to any one of the preceding claims, further comprising one or more heterologous moieties.

6. A MDM2 inhibitor according to claim 5, wherein the heterologous moiety is linked to a side chain of P at a residue , or to a N-terminal or C-terminal functional group.

7. A MDM2 inhibitor according to claim 5 or claim 6, wherein the heterologous moiety is a membrane transit moiety.

8. A MDM2 inhibitor according to claim 7, wherein the membrane transit moiety is a cell penetrating peptide.

9. A MDM2 inhibitor according to claim 8, wherein the cell penetrating peptide forms a fusion protein with P, e.g. wherein the cell penetrating peptide is located N-terminal of the core sequence and is optionally spaced from the N-terminus of the core sequence by a linker peptide.

10. An MDM2 inhibitor according to claim 8 or claim 9, wherein the cell penetrating peptide is polyarginine, poly-D-arginine, GRKKRRQRRR, Grkkrrqrrr, cyclo[GRKKRRQRRR] or cyclo[Grkkrrqrrr],00884900212111. A MDM2 inhibitor according to claim 10, wherein wherein the cell penetrating peptide is_Arg4 w or [D-Arg]4 w, optionally Args, Argo, [D-Arg]s or [D-Arg]g.

12. A MDM2 inhibitor according to any one of the preceding claims, wherein the core sequence has the formula:008849002122X1 -X2-X3-X4-X5-X6-X7-X8-X9-X10-X11 -X12 whereinXI is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;X2 is selected from Gin, Phe, Tyr, Leu, lie, Gly, Met, Cys, His, Thr, Pro, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;X3 is selected from Pro, Gly, Cys, His, Thr, Gin, Asn and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or a residueX4 is selected from lie, Trp, Phe, Tyr, Leu, Vai, Gly, Met, Cys, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof, Aib, or is a residue <D or ;X5 is selected from Gin, Trp, Phe, Leu, lie, Vai, Met, His, Thr, Pro, Ser and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;X6 is selected from Met, Tyr, Leu, lie, Vai, Gly, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N- substituted glycine analogue thereof;X7 is selected from lie, Phe, Tyr, Leu, Vai, Met, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ^P;X8 is selected from Vai, Trp, Phe, Tyr, Leu, lie, Gly, Met, Cys, His, Thr, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, Aib, or is a residue 41;X9 is selected from Leu, Trp, Phe, Tyr, lie, Vai, Gly, Met, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residueX10 is selected from Thr, Phe, Leu, lie, Vai, Gly, Met, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;XI I is selected from Tyr, Trp, Phe, Leu, lie, Vai, Gly, Met, Cys, His, Thr, Pro, Gin, Asn, Ser, Glu, Arg and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;X12 is selected from Phe, Trp, Tyr, Leu, lie, Vai, Gly, Met, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof; wherein, if X4 is a residuethen residue X7 or X8 is a residue * and vice versa, a maximum of one residue ^P is present, and, when present, the side chains of residues <D and 'P form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety;008849002123 and wherein the core sequence is:(i)(a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;(b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);(c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);(ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or(iii) a peptoid, N-methyl or retro-inverso version of (i) or (ii).

13. A MDM2 inhibitor according to claim 12, wherein:X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;X2 is selected from Gin, Phe, Tyr, Leu, He, Gly, Met, Cys, His, Thr, Pro, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;X3 is selected from Pro, Gly, Cys, His, Thr, Gin, Asn and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residueX4 is selected from He, Trp, Phe, Tyr, Leu, Vai, Gly, Met, Cys, His, Thr, Pro, Gin and Ser, or a D-form, N- methyl, or N-substituted glycine analogue thereof, Aib, or is a residueX5 is selected from Gin, Trp, Phe, Leu, lie, Vai, Met, His, Thr, Pro, Ser and Lys, or a D-form, N-methyl, or N-substituted glycine analogue thereof;X6 is selected from Met, Tyr, Leu, lie, Vai, Gly, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N- substituted glycine analogue thereof;X7 is selected from lie, Phe, Tyr, Leu, Vai, Met, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residueX8 is selected from Vai, Trp, Phe, Tyr, Leu, lie, Gly, Met, Cys, His, Thr, Asn, Ser, Asp and Glu, or a D- form, N-methyl, or N-substituted glycine analogue thereof, Aib, or is a residue008849002124X9 is selected from Leu, Trp, Phe, Tyr, He, Vai, Gly, Met, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residueX10 is selected from Thr, Phe, Leu, He, Vai, Gly, Met, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;X11 is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;X12 is selected from Phe, Trp, Tyr, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residuethen residue X7 or X8 is a residue and vice versa, a maximum of one residue is present, and, when present, the side chains of residues <D and 4* form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:(i)(a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;(b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);(c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);(ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or(iii) a peptoid, N-methyl or retro-inverso version of (i) or (ii).

14. A MDM2 inhibitor according to claim 12 or claim 13, wherein:X1 is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;008849002125X2 is selected from Gin, Gly, His, Thr, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residueX3 is selected from Pro, Gly and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;X4 is selected from He, Trp, Tyr, Leu, Vai, Gly, His, Thr, Gin and Ser, or a D-form, N-methyl, or N- substituted glycine analogue thereof, Aib, or is a residue orX5 is selected from Gin, His, Thr and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof;X6 is selected from Met, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof;X7 is selected from He, Phe, Tyr, Leu, Vai, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue1;X8 is selected from Vai, Phe, Tyr, Leu, lie, Thr, Asn, Ser, Asp and Glu, or a D-form, N-methyl, or N- substituted glycine analogue thereof, Aib, or is a residue 4^;X9 is selected from Leu, Phe, Tyr, lie, Vai, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;X10 is selected from Thr, Gly, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;X11 is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;X12 is selected from Phe, Trp, Tyr, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residuethen residue X7 or X8 is a residue and vice versa, a maximum of one residue1is present, and, when present, the side chains of residues 4) and form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:(i)(a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1) or an all-D form thereof;008849002126(b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);(c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);(ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or(iii) a peptoid, N-methyl version or retro-inverso form of (i) or (ii).

15. A MDM2 inhibitor according to any one of claims 12 to 14, wherein:XI is selected from Arg and D-Arg, or an N-methyl or N-substituted glycine analogue thereof;X2 is selected from Gin, Gly, His, Thr, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residueX3 is selected from Pro, Gly and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;X4 is selected from He, Gly, His, Thr, Gin and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof, Aib, or is a residueX5 is selected from Gin, His, Thr and Ser, or a D-form, N-methyl, or N-substituted glycine analogue thereof;X6 is selected from Met, His, Thr, Gin, Ser and Asp, or a D-form, N-methyl, or N-substituted glycine analogue thereof;X7 is selected from He, Thr and Gin, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue MJ;X8 is selected from Vai, Thr, Asn, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, Aib, or is a residue J;X9 is selected from Leu, Thr, Gin, Ser and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof, or is a residue ;X10 is selected from Thr, Gly, His, Gin, Ser, Asp and Glu, or a D-form, N-methyl, or N-substituted glycine analogue thereof;XI I is selected from Tyr, Trp, Phe, Leu, lie and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof;008849002127X12 is selected from Phe, Trp, Tyr, Leu, He and Vai, or a D-form, N-methyl or N-substituted glycine analogue thereof; wherein, if X4 is a residue then residue X7 or X8 is a residue * and vice versa, a maximum of one residue 41is present, and, when present, the side chains of residues 0 and MJ form a covalent bond; where the side chain of any residue forms a covalent bond with a heterologous moiety; and wherein the core sequence is:(i)(a) Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1 ) or an all-D form thereof;(b) Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);(c) [D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 3);(ii) a core sequence which differs from any one of (a), (b) or (c) by no more than 5 substitutions; or(iii) a peptoid, N-methyl version or retro-inverso form of (i) or (ii).

16. A MDM2 inhibitor according to any one of claims 12 to 15, wherein the core sequence has the formula:X1-Gln-Pro-X4-Gln-X6-X7-X8-X9-Thr-X11-X12 whereX1 is selected from Arg and D-ArgX4 is He, Gin, Aib, or is a residue <t> orX6 is selected from Met and Thr, or a D-form thereof;008849002128X7 is He, or is a residueX8 is Vai, Asp, Aib, or is a residue1;X9 is Leu, or is a residueX11 is selected from Tyr and Leu, or a D-form thereof;X12 is selected from Phe and D-Phe17. A MDM2 inhibitor according to any one of the preceding claims, wherein the core sequence comprises a sequence selected from:Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe (SEQ ID NO: 1);Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe] (SEQ ID NO: 2);[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; andArg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe; or a peptoid, N-methyl or retro-inverso version thereof.

18. A MDM2 inhibitor according to any one of claims 1 to 16, wherein the core sequence comprises a sequence selected from:[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Asp-Leu-Thr-[D-Leu]-[D-Phe];[D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];[D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Asp-Leu-Thr-[D-Leu]-[D-Phe]; and[D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-Leu-Thr-[D-Leu]-[D-Phe]; or a peptoid, N-methyl or retro-inverso version thereof.

19. A MDM2 inhibitor according to any one of claims 1 to 16, wherein the core sequence comprises a sequence selected from:Arg-Gln-Pro-dJ-Gln-Met-lle-MJ-Leu-Thr-Leu-Phe;Arg-Gln-Pro-<U-Gln-Met-lle-MJ-Leu-Thr-[D-Leu]-[D-Phe];[D-Arg]-Gln-Pro-<U-Gln-[D-Thr]-lle-MJ-Leu-Thr-[D-Leu]-[D-Phe];Arg-Gln-Pro-dJ-Gln-Met-lle-MJ-Leu-Thr-Tyr-Phe;Arg-GIn-Pro-O-GIn-Met-'+’-Val-Leu-Thr-Leu-Phe;Arg-Gln-Pro-(U-Gln-Met- ’-Val-Leu-Thr-[D-Leu]-[D-Phe];008849002129[D-Arg]-Gln-Pro-0-Gln-[D-Thr]-*-Val-Leu-Thr-[D-Leu]-[D-Phe]; andArg-GIn-Pro- -GIn-Met-'+’-Val-Leu-Thr-Tyr-Phe; where the side chains of residues and1form a covalent bond; or a peptoid, N-methyl or retro-inverso version thereof.

20. A MDM2 inhibitor according to any one of claims 1 to 16, wherein the disruptor component P comprises a sequence selected from:^-Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Leu-Phe; -Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];<-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];^-Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe;Arg-GIn-Pro-lle-GIn-Met-lle-Val-^-Thr-Leu-Phe;Arg-Gln-Pro-lle-Gln-Met-lle-Val-<-Thr-[D-Leu]-[D-Phe];[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val- -Thr-[D-Leu]-[D-Phe]; andArg-GIn-Pro-lle-GIn-Met-lle-Val-^-Thr-Tyr-Phe; where the side chain of the residue ( forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof.

21. A MDM2 inhibitor according to any one of claims 1 to 16, wherein the disruptor component P comprises a sequence selected from:<-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Asp-Leu-Thr-[D-Leu]-[D-Phe]; - [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]; - [D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Asp-Leu-Thr-[D-Leu]-[D-Phe]; - [D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-Leu-Thr-[D-Leu]-[D-Phe];[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Asp-<-Thr-[D-Leu]-[D-Phe];[D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val- -Thr-[D-Leu]-[D-Phe];[D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Asp-<-Thr-[D-Leu]-[D-Phe]; and008849002130[D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-<-Thr-[D-Leu]-[D-Phe]; where the side chain of the residue ( forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof.

22. A MDM2 inhibitor according to any one of claims 1 to 16, wherein the disruptor component P comprises a sequence selected from:^-Arg-GIn-Pro-O-GIn-Met-lle-'+'-Leu-Thr-Leu-Phe;<-Arg-Gln-Pro-0-Gln-Met-lle-^-Leu-Thr-[D-Leu]-[D-Phe];<-[D-Arg]-Gln-Pro-(D-Gln-[D-Thr]-lle-^-Leu-Thr-[D-Leu]-[D-Phe];(-Arg-GIn-Pro-cb-GIn-Met-lle-^P-Leu-Thr-Tyr-Phe;(-Arg-GIn-Pro-cb-GIn-Met-^P-Val-Leu-Thr-Leu-Phe;<-Arg-Gln-Pro-0-Gln-Met-^-Val-Leu-Thr-[D-Leu]-[D-Phe];<-[D-Arg]-Gln-Pro-(D-Gln-[D-Thr]-^-Val-Leu-Thr-[D-Leu]-[D-Phe];(-Arg-GIn-Pro-cb-GIn-Met-^P-Val-Leu-Thr-Tyr-Phe;Arg-Gln-Pro-<t>-Gln-Met-lle-'4J-£-Thr-Leu-Phe;Arg-Gln-Pro-<D-Gln-Met-lle-^-<-Thr-[D-Leu]-[D-Phe];[D-Arg]-Gln-Pro-ct>-Gln-[D-Thr]-lle-^-<-Thr-[D-Leu]-[D-Phe];Arg-Gln-Pro-<t>-Gln-Met-lle-'4J-£-Thr-Tyr-Phe;Arg-GIn-Pro-dJ-GIn-Met-'+’-Val-^-Thr-Leu-Phe;Arg-Gln-Pro-(U-Gln-Met-4’-Val-<-Thr-[D-Leu]-[D-Phe];[D-Arg]-Gln-Pro-<b-Gln-[D-Thr]-MJ-Val <-Thr-[D-Leu]-[D-Phe]; andArg-GIn-Pro-O-GIn-Met-'+’-Val-^-Thr-Tyr-Phe; where the side chains of residues <t> and form a covalent bond; and where the side chain of the residue £ forms a covalent bond with a heterologous moiety; or a peptoid, N-methyl or retro-inverso version thereof.00884900213123. A MDM2 inhibitor according to any one of the preceding claims, having the formulaZ-L-P whereZ is a cell penetrating peptide;P is the disruptor component; andL is a linker peptide sequence (e.g. of 1-10 amino acids, e.g. of 1-5 amino acids), or represents a bond between Z and P; or a peptoid, N-methyl or retro-inverso version thereof.

24. A MDM2 inhibitor according to claim 23, having the formulaY1 -Z-L-P- Y2 whereY1 is H, Ac cr a heterologous moiety (e.g. H or Ac);Z is a cell penetrating peptide;P is the disruptor component;L is a linker peptide sequence (e.g. of 1-10 amino acids, e.g. of 1-5 amino acids), or represents a bond between Z and P; andY2 is OH, NH2 or a heterologous moiety (e.g. OH or NH2).

25. A MDM2 inhibitor according to any one of the preceding claims, comprising the sequence:Arg-GIn-Pro-lle-GIn-Met-lle-Val-Leu-Thr-Tyr-Phe;(Stearoyl)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe;[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe;[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Tyr]-[D-Phe];[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Leu-Phe;[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];[D-Arg]8-Cys-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];008849002132Cys(-Ac-[D-Arg]9-NH2)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];[D-Cys](-Ac-[D-Arg]9-NH2)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];Cys-(-C12-cCPP-C)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe];Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-Leu-Thr-[D-Leu]-[D-Phe];Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-hCys-Gln-[D-Thr]-lle-hCys-Leu-Thr-[D-Leu]-[D-Phe];Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Pra-Gln-[D-Thr]-lle-Abu(N3)-Leu-Thr-[D-Leu]-[D-Phe]; orCys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Cys-Gln-[D-Thr]-lle-Cys-Leu-Thr-[D-Leu]-[D-Phe]; or a peptoid, N-methyl or retro-inverso version thereof.

26. A MDM2 inhibitor selected from:Ac-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe-NH2;(Stearoyl)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe-NH2(DRx-97-S);Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Tyr-Phe -NH2(DRx-97-R);Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Tyr]-[D-Phe]-NH2(DRx-97D-R);Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-Leu-Phe-NH2(DRx-98R);Ac-[D-Arg]9-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-98D-R);Ac-[D-Arg]8-Cys-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-990);Ac-Cys(-Ac-[D-Arg]9-NH2)-Arg-Gln-Pro-lle-Gln-Met-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx-991 );Ac-[D-Cys](-Ac-[D-Arg]9-NH2)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(DRx- 992);Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(7175);Cys-(-C12-cCPP-C)-[D-Arg]-Gln-Pro-lle-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(7176);Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Gln-Gln-[D-Thr]-lle-Val-Leu-Thr-[D-Leu]-[D-Phe]-NH2(1724);Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Aib-Gln-[D-Thr]-lle-Aib-Leu-Thr-[D-Leu]-[D-Phe]-NH2(1211 );Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-hCys-Gln-[D-Thr]-lle-hCys-Leu-Thr-[D-Leu]-[D-Phe]-NH2(3276);Cys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Pra-Gln-[D-Thr]-lle-Abu(N3)-Leu-Thr-[D-Leu]-[D-Phe]-NH2(3277); andCys-(-C12-cCPP-K)-[D-Arg]-Gln-Pro-Cys-Gln-[D-Thr]-lle-Cys-Leu-Thr-[D-Leu]-[D-Phe]-NH2(3275);008849002133 or a peptoid, N-methyl or retro-inverso version thereof.

27. A MDM2 inhibitor according to any one of claims 1 to 26 for use in the treatment of cancer, inflammatory disease, dementia or a neurodegenerative disease, nephropathy, or heart or cardiovascular disease.

28. A MDM2 inhibitor for use according to claim 27, wherein:(a) the cancer neuroblastoma, a myeloproliferative neoplasm (e.g. polycythemia vera or myelofibrosis), leukaemia (e.g., acute myeloid leukaemia and subtypes thereof), lung cancer, colorectal cancer (e.g., poorly differentiated colorectal cancer), osteosarcoma, melanoma, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), prostate cancer (e.g., neuroendocrine prostate cancer), rhabdomyosarcoma, or glioma (e.g., paediatric high-grade glioma);(b) the inflammatory disease is an autoimmune disease, e.g. rheumatoid arthritis, systemic lupus erythaematosus (SLE), pancreatitis or gastritis;(c) the dementia or neurodegenerative disease is, or is associated with, for example, fragile X syndrome, Parkinson’s disease or Alzheimer’s disease;(d) the nephropathy is autosomal dominant polycystic kidney disease, renal fibrosis or diabetic nephropathy; or(e) wherein the cardiovascular disease is myocardial infarction or atherosclerosis.

29. A MDM2 inhibitor for use according to claim 28, wherein the acute myeloid leukaemia subtype is acute promyelocytic leukaemia.

30. A MDM2 inhibitor for use according to claim 27 or claim 28, wherein the MDM2 inhibitor is for use in the treatment of cancer and wherein the treatment further comprises administering a differentiationinducing agent to a subject.

31. A MDM2 inhibitor for use according to claim 30, wherein the differentiation-inducing agent is selected from the group consisting of retinoic acid and retinoic acid derivatives, arsenic trioxide (ATO), cAMP, sodium butyrate, and cytokines.00884900213432. A MDM2 inhibitor for use according to claim 30 or claim 31 , wherein the differentiation-inducing agent is administered simultaneously as the MDM2 inhibitor or wherein the differentiation-inducing agent is administered separately to the MDM2 inhibitor.

33. A composition comprising an MDM2 inhibitor according to any one of claims 1 to 26 and a differentiation-inducing agent for use in the treatment of cancer.

34. A composition for use according to claim 33, wherein the differentiation-inducing agent is selected from the group consisting of retinoic acid and retinoic acid derivatives, arsenic trioxide (ATO), cAMP, sodium butyrate, and cytokines.

35. A composition for use according to claim 33 or claim 34, wherein the cancer is neuroblastoma, a myeloproliferative neoplasm (e.g. polycythemia vera or myelofibrosis), leukaemia (e.g., acute myeloid leukaemia and subtypes thereof), lung cancer, colorectal cancer (e.g., poorly differentiated colorectal cancer), osteosarcoma, melanoma, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), prostate cancer (e.g., neuroendocrine prostate cancer), rhabdomyosarcoma, or glioma (e.g., paediatric high-grade glioma).

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