Modified ezetimibe drug for cancer treatment

Abstract

This invention relates to a modified ezetimibe having the structure of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer by oral administration through inhibition of HDM2 / HDM4-mediated suppression of p53, wherein the binding affinity and oral bioavailability of the modified ezetimibe for targeting of HDM2, HDM4 (also known as HDMX) and more particularly, both HDM2 and HDM4 is enhanced compared with unmodified ezetimibe. (I)

Description

[0001] MODIFIED EZETIMIBE DRUG FOR CANCER TREATMENT

[0002] FIELD OF THE INVENTION THIS INVENTION relates to an anti-cancer drug that is a modification of the drug ezetimibe, the modified drug having enhanced pharmacokinetics and pharmacodynamics for the anticancer targeting of HDM2, HDM4 (also known as HDMX) and more particularly, both HDM2 and HDM4, compared with unmodified ezetimibe.

[0003] BACKGROUND TO THE INVENTION

[0004] The tumour suppressor protein p53 is involved in a number of important biological processes that are crucial for carcinogenesis, including the cell cycle, apoptosis, DNA repair, angiogenesis, glucose metabolism and innate immunity. It is a transcription factor that acts as a regulator of the human homolog of murine double minute 2 (HDM2) gene in chromosome 12q14.3-q15 in a feedback loop where p53 activates expression of the HDM2 gene and HDM2 regulates p53 by controlling its transport out of the nucleus thereby making it unavailable to its gene targets. This inhibits its transcription function or promotes its degradation by proteasomes using ubiquitinligase activity. HDM2 has a hydrophobic binding pocket to which p53 binds by means of a peptide in its transactivation domain. This pocket is a key target for drugs that inhibit the p53-HDM2 interaction.

[0005] The applicant has previously shown that ezetimibe is a useful small molecule for targeting the HDM2 hydrophobic pocket. Ezetimibe, however, has structural vulnerabilities that hinder its oral administration as an anti-cancer agent, such as its conversion by metabolic enzymes in the intestines. This results in negligible bioavailability of ezetimibe and as such, in its parent form, it is unsuitable for use in the treatment of colonic cancers. In order to address this, the applicant developed a modified ezetimibe as disclosed in PCT patent application no. PCT / IB2021 / 057046 in order to decrease its degradation by metabolic enzymes in the intestine and make it suitable for treating colon and colorectal cancers in particular.

[0006] The human homolog of murine double minute 4 (HDM4 or HDMX) gene is in chromosome 1q32 and encodes a protein similar in structure to HDM2, also able to bind to and inhibit the transactivation of p53 although without the E3 ligase activity. HDM4 protein stabilizes the p53- HDM2 complex thereby enhancing HDM2 E3 ligase activity. HDM2 and HDM4 have also been shown to independently and cooperatively regulate proteasome-mediated degradation of the cyclin-dependent kinase inhibitor, p21 , in the G1 and early S phases of the cell cycle.

[0007] HDM4 also has a p53-binding pocket and inhibits the transactivation of HDM2 by binding to the N-terminal domain of p53. Although a comparative analysis of the critical residues in the p53 binding pockets (p53BD) of HDM2 and HDM4 shows that these are highly similar, these two proteins have been shown to have significant differences in their drug interactions.

[0008] Therefore, new small molecule drug targets for inhibition of both HDM2 and HDM4 that exhibit enhanced metabolic stability and bioavailability compared with ezetimibe, particularly through improved permeability and good oral absorption, would be highly beneficial in the treatment of cancer.

[0009] SUMMARY OF THE INVENTION

[0010] According to a first aspect of the invention there is provided a compound having the structure of Formula (I):

[0011]

[0012] (I) or a pharmaceutically acceptable salt thereof.

[0013] The compound or a pharmaceutically acceptable salt thereof may have enhanced binding affinity to HDM2, HDM4, or both HDM2 and HDM4 and in particular to the hydrophobic binding pocket of HDM2, HDM4, or both HDM2 and HDM4 to which p53 binds relative to unmodified ezetimibe. The compound or a pharmaceutically acceptable salt thereof may therefore prevent the binding of HDM2, HDM4, or both HDM2 and HDM4 to p53, thereby increasing the levels of p53 in a cell.

[0014] The compound or a pharmaceutically acceptable salt thereof may have enhanced oral bioavailability including in the intestine due to reduced degradation, and in particular glucuronidation relative to unmodified ezetimibe.

[0015] The compound or a pharmaceutically acceptable salt thereof may have both enhanced binding affinity to HDM2, HDM4, or both HDM2 and HDM4, and enhanced oral bioavailability relative to unmodified ezetimibe. According to a second aspect of the invention there is provided a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0016] According to a third aspect of the invention there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a composition according to the invention for use in a method of treating a cancer.

[0017] According to a fourth aspect of the invention there is provided use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a cancer.

[0018] The cancer may be a cancer in which there are elevated levels of HDM2, HDM4, or both HDM2 and HDM4 or where HDM2, HDM4, or both HDM2 and HDM4 is overexpressed. The cancer may include colon cancer, colorectal cancer, sarcoma, glioma, lymphoma, breast cancer, lung cancer, liver cancer, esophagogastric cancer and gynaecological cancers. More preferably, the cancer is selected from colon cancer, colorectal cancer and esophagogastric cancer.

[0019] The compound or a pharmaceutically acceptable salt thereof may have enhanced binding to the hydrophobic binding pocket of HDM2, HDM4, or both HDM2 and HDM4 relative to unmodified ezetimibe, and increase the levels of active p53 in a cell to greater levels than unmodified ezetimibe. This results in an increase in p53-mediated cell death of cancer cells relative to the use of unmodified ezetimibe.

[0020] The compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition or the medicament is preferably formulated for oral administration. For example, the oral formulation may be as a tablet or capsule.

[0021] According to a fifth aspect of the invention there is provided a method of treating a cancer by administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. The cancer is preferably characterised by high levels or overexpression of HDM2, HDM4, or both HDM2 and HDM4 levels. The method may comprise enhanced binding of the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the hydrophobic binding pocket of HDM2, HDM4, or both HDM2 and HDM4 levels and increased levels of p53 in the cell relative to a method of treatment with unmodified ezetimibe. The compound or a pharmaceutically acceptable salt thereof may promote p53-mediated cell death of cancer cells.

[0022] The cancer may be selected from colon cancer, colorectal cancer, sarcoma, glioma, lymphoma, breast cancer, lung cancer, liver cancer, esophagogastric cancer and gynaecological cancer. More preferably, the cancer is selected from colon cancer, colorectal cancer and esophagogastric cancer.

[0023] DESCRIPTION OF FIGURES

[0024] The invention will now be described in more detail with reference to the Example hereunder, and the accompanying drawings.

[0025] In the drawings:

[0026] Figure 1 shows an annotated diagram of ezetimibe including hydroxyl groups that are commonly glucuronidated: the solid circle indicates most commonly glucuronidated, and the double solid circle indicates less commonly glucuronidated, and the dashed ovals indicate the R-groups that were altered;

[0027] Figure 2 shows a graph of the induced fit docking of the generated ezetimibe analogue to HDM2 and HDM4. The average IFD score is the average score from all resultant poses for the analogue towards either HDM2 (grey) or HDM4 (black); and

[0028] Figure Error! No text of specified style in document. 2D representation of the docking top pose of HDM2 and HDM4 complexed with MTS_42. (A) HDM2-31 complex, IFD score -210.56 kcal / mol, (B) HDM4-31 complex, IFD score -207.27 kcal / mol.

[0029] DETAILED DESCRIPTION

[0030] This invention relates to a compound having the structure of Formula (I):

[0031]

[0032] or a pharmaceutically acceptable salt thereof that is a modification of the drug ezetimibe, the modified drug having enhanced pharmacokinetics and pharmacodynamics for the anticancer targeting of HDM2, HDM4 (also known as HDMX) and more particularly, both HDM2 and HDM4, compared with unmodified ezetimibe. The invention further relates to methods of use of the compound of Formula (I), or a composition comprising the compound in the treatment of cancer.

[0033] The following description of the invention is provided as an enabling teaching of the invention, is illustrative of the principles of the invention and is not intended to limit the scope of the invention. It will be understood that changes can be made to the embodiment / s depicted and described, while still attaining beneficial results of the present invention. Furthermore, it will be understood that some benefits of the present invention can be attained by selecting some of the features of the present invention without utilising other features. Accordingly, those skilled in the art will recognise that modifications and adaptations to the present invention are possible and can even be desirable in certain circumstances, and are a part of the present invention.

[0034] EXAMPLE Proteins

[0035] The protein targets utilised in the associated study include HDM2 and HDM4 (uniport accession numbers: Q00987 and 015151). The study did not utilize the full-length versions of these respective proteins, rather it assessed their p53 binding domains only. Hence the PDB crystal structures of their respective proteins included: HDM2 (PDB code: 4HG7) and HDM4 (PDB code: 7C3Q).

[0036] Lead compound (Ezetimibe)

[0037] The lead compound for this study was ezetimibe (see Figure 1), but the pharmacokinetics of this compound exhibited inferior bioavailability and target efficacy. Hence, the goal of this study was to enhance the target efficacy, absorption, particularly oral absorption, and associated metabolism of the lead compound. Figure 1 below shows the specific R-groups that were targeted for alteration in order to enhance said characteristics. The choice of alternative R-group was determined through enumeration of a solubility database and a reaction-based database. Thereafter, the ezetimibe analogue was subjected to pharmacokinetic analysis and IFD for HDM2 / HDM4 following the above-mentioned protocols.

[0038] Pharmacokinetic analysis

[0039] Prior to pharmacokinetic analysis and other downstream in silico experiments, the ligands were prepared. Ligand preparation was employed to rectify structural issues, such as bond length, compound charge and chirality from ligands models generated using Schrodinger’s 2D sketcher. The LigPrep program was employed for ligand preparation, with the following settings: limit ligand size to 500 atoms, utilize the OPLS4 force field, generate possible states at pH 7.0 ± 2.0 using the utility program Epik. The desalt and generate tautomers options were selected for, and with regards to stereoisomers, chirality’s were determined from the 3D structure of the ligand.

[0040] QikProp is an accurate ADME prediction program; it predicts significant descriptors and many pharmaceutically relevant properties (see Table 1 below) of organic molecules. Not all these properties were relevant to this study. The program was run using fast mode and set to identify 5 similar compounds to the one that was being analysed.

[0041] Table 1 : QikProp properties used to estimate the pharmacokinetics of a few known HDM2 and / or HDM4 inhibitors, in addition to ezetimibe.

[0042] Property Description Accepted values Molecular weight The molecular weight of the molecule in 500 - 2000 Daltons.

[0043] HB Donor An estimated number of hydrogen bonds that 0 -6

[0044] could be donated by the subject molecule to surrounding water molecules (Abraham et al.,

[0045] 1994).

[0046] HB Acceptor An estimated number of hydrogen bonds that 2 -20

[0047] could be accepted by the subject molecule to

[0048] surrounding water molecules (Abraham et al.,

[0049] 1994).

[0050] #metab$ Number of probable metabolic reactions - 1 - 8

[0051] these may include various forms of

[0052] oxidations, dealkylations or hydroxylations.

[0053] #rtvFG Number of reactive functional groups on the 0-2

[0054] subject compound.

[0055] QPIogPo / w Estimated octanol / water partition coefficient -2.0 -6.5

[0056] (Duffy and Jorgensen, 2000).

[0057] QPIogS Estimated aqueous solubility - log (mol. dm-3) -6.5 - 0.5

[0058] (Jorgensen and Duffy, 2000, 2002).

[0059] QPIogHERG Estimated ICso value for blockage of hERG K+< -5

[0060] channels (Cavalli etal., 2002).

[0061]

[0062] QPPCaco Estimated Caco-2 cell permeability in nm.s’1< 25 poor, (a model for the gut-blood barrier) (Yazdanian

[0063] > 500 great. etal., 1998).

[0064] QPIogBB Estimated brain / blood partition coefficient -3.0 - 1.2

[0065] (Keldereta / ., 1999; Luco, 1999).

[0066] QPPMDCK Estimated MDCK cell permeability in nm.s’1< 25 poor,

[0067] (a model for the blood brain barrier) (Irvine et

[0068] > 500 great al., 1999).

[0069] QPIogKHSA Estimated of binding to human serum albumin -1.5 - 1.5

[0070] (Colmenarejo, Alvarez-Pedraglio and

[0071] Lavandera, 2001).

[0072] Percent Human Estimated human oral absorption (Stenberg > 80% high Oral Absorption et al., 2001).

[0073] < 25% poor RuleOfFive Number of violations of Lipinski’s rule of five: < 4

[0074] molecular weight < 500, QPIogPo / w < 5, HB

[0075] Donor < 5, HB Acceptor < 10 (Lipinski, 2004).

[0076] RuleOfThree Number of violations of Jorgensen’s rule of < 3

[0077] three: QPIogS > -5.7, QPPCaco > 22 nm / s,

[0078] #metab$ < 7 (Jorgensen, 2009).

[0079] Similar Identify of 5 similar compounds to the one - compounds that was being analysed

[0080]

[0081] To enhance the efficacy, absorption and reduce the glucuronidation associated metabolism of ezetimibe, the compound was altered (see methods and materials below). Using the top pose ezetimibe HDM2 / HDM4 complexes (from initial docking), the ezetimibe-analogue was generated. Pharmacokinetic and docking studies were performed on the analogue, the respective results thereof are as follows.

[0082] Docking studies Flexible docking refers to a kind of docking simulation that considers the flexibility of the receptor and the ligand. Conventional molecular docking frequently makes the assumption that the ligand and receptor have rigid structures, which might not adequately capture the flexibility and dynamic characteristics of biological macromolecules. Flexible docking was utilized in this study to approximate the binding affinity of the analogues toward HDM2 / HDM4. This score was compared to docking scores of known HDM2 / HDM4 inhibitors.

[0083] The flexible docking protocol used was the Induced Fit Docking (IFD) protocol -Schrodinger Release 2021-2. The binding affinity approximation of a ligand to a receptor is calculated by the IFD score:

[0084] IFDScore = 1.0*Prime_Energy + 9.057*GlideScore + 1 ,428*Glide_Ecoul (The exact composition of:Prime_Energy, Glide_Score and Glide_Ecoul is proprietary to Schrodinger).

[0085] The employed IFD protocol used the HDM2 nutlin-3a complex and HDM4 nutlin-3a complex, PDB crystal structures, using the standard protocol, which generated up to 20 poses. The nultin-3a ligands were used as the box centre with the box size set to “dock ligands similar in size to workspace ligand”. With regards to ligand settings, conformational sampling was set to “sample ring conformations” with an energy window of 2.5 kcal / mol and amide bonds set to “penalize nonplanar conformation”. Prime refinement was set to refine residues within 5.0 A of ligand poses and the “Optimize side chains” option was selected. Glide redocking was set to redock structures within 30.0 kcal / mol of the best structure, and within the top 20 structures overall with standard precision. The listed settings are the suggested default settings for most IFD simulations according to Schrodinger suite.

[0086] Results

[0087] Lead optimization

[0088] The generated analogue, (3R,4S)-4-(4-amino-6-(ethyl(propyl)amino)-1 ,3,5-triazin-2-yl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)azetidin-2-one (referred to as MTS_42), is shown in the Formula I below, with the original phenyl group substituted for a 4-amino-6-(ethyl(propyl)amino)-1.3.5-triazin-2-yl . Idifitener

[0089] lMW mo_

[0090] dHBonor

[0091] HBt accp

[0092] #btmea

[0093] #FGtrv

[0094] QPIP / ogow

[0095] QPISog

[0096]

[0097] QPIHERGog

[0098] Formula I

[0099] QPPCaco

[0100] QPIBBog

[0101] Pharmacokinetic approximation

[0102] From Table 2 below, ezetimibe (“EZE”) has the lowest mo QPPMDCKlecular weight, highest permeability (both Caco-2 and MDCK), and good oral absorption, while although QPIKhogsa

[0103] MTS_42 shows the least favourable properties in permeability it still complies with the H Olmanrau

[0104] rules and has good oral absorption. Due to the lower glucuronidation o Abitsorponf MTS_42

[0105] (%» compared with ezetimibe, MTS_42 is superior, as ezetimibe is susceptible to RlOfFieeuv glucuronidation and thus has low bioavailability.

[0106] RlOfThereeu Table 2: QikProp analysis of the generated ezetimibe analogues.

[0107] EZE 409 2 4.5 3 1 5.14 -6.86 -6.84 612.5 -0.91 948.2 0.86 94.0 1 1

[0108]

[0109] MTS_42 497 3 7.7 2 1 5.33 -7.75 -6.95 415.7 -1.51 624.1 0.83 92.1 1 1

[0110] Flexible docking

[0111] With regards to IFD, compound MTS_42 exhibited an IFD score greater than ezetimibe (see Figure 2). This thus indicates an increase in efficacy towards HDM2 / HDM4. Figure 3 indicates the 2D representation of the top poses for HDM2 and HDM4 complexed with MTS_42.

[0112] The 2D representation of molecular docking poses shown in Figure 3 illustrates compound MTS_42 interacting with several amino acids, within the binding pocket of HDM2 (left) and HDM4 (right). Key interactions include hydrogen bonds, hydrophobic contacts, and Pi-cation interactions, indicating a strong binding affinity. Several key residues, such as LEU, PHE, TYR, ILE, VAL and MET, seem to be involved in hydrophobic interactions.

[0113] Discussion

[0114] The current study explored the optimization of the lead compound ezetimibe by modifying specific R-groups to enhance its pharmacokinetics and efficacy in targeting HDM2 and HDM4 proteins. These proteins play a pivotal role in the p53 tumour suppressor pathway, and inhibiting their activity can restore the p53 function, a promising approach in cancer therapy. The study utilized truncated versions of HDM2 and HDM4, focusing solely on their p53-binding domains, which were essential for binding interactions with the optimized compounds. The PDB structures of these truncated proteins (4HG7 for HDM2 and 7C3Q for HDM4) were employed to model the docking interactions.

[0115] Ezetimibe, the initial lead compound, demonstrated suboptimal bioavailability and target efficacy. Consequently, the modifications aimed at enhancing absorption and reducing susceptibility to metabolism via glucuronidation. Through ligand preparation and pharmacokinetic analysis using LigPrep and QikProp, analogues of ezetimibe were generated and evaluated. The pharmacokinetic analysis revealed that ezetimibe, despite showing favourable permeability and good oral absorption, exhibited susceptibility to glucuronidation, reducing its overall bioavailability. The generated analogue, MTS_42, on the other hand, showed distinct advantages over ezetimibe in terms of both oral absorption and metabolic stability. The results of this study suggests that targeting the R-groups in ezetimibe can mitigate glucuronidation, a key limiting factor for bioavailability in the parent compound. The docking studies using flexible docking protocols further highlighted the superiority of the modified analogue MTS_42 which exhibited higher binding affinities towards HDM2 and HDM4 compared to ezetimibe. The IFD scores indicate a superior interaction with both targets, and therefore enhanced inhibition of HDM2 / HDM4-mediated suppression of p53. This improvement in docking scores underscores the potential therapeutic value of modified analogue MTS_42 in restoring p53 function in cancer cells.

[0116] In conclusion, the modified analogue MTS_42 exhibited enhanced pharmacokinetic profiles and binding affinities to HDM2 and HDM4, combining favourable oral absorption with strong binding interactions, thereby overcoming metabolic limitations existing with the original ezetimibe compound, and improving target specificity.

[0117] REFERENCES

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[0120] Colmenarejo G, Alvarez-Pedraglio A, Lavandera JL. Cheminformatic models to predict binding affinities to human serum albumin. J Med Chem. 2001 Dec 6;44(25):4370-8. doi: 10.1021 / jm010960b. PMID: 11728183.

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Claims

CLAIMS1. A modified ezetimibe compound having the structure of Formula (I):or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer by oral administration in a subject in need thereof, wherein binding affinity and oral bioavailability, including intestinal bioavailability, of the modified ezetimibe for targeting of HDM2, HDM4 (also known as HDMX) or both HDM2 and HDM4 is enhanced compared with unmodified ezetimibe.

2. The modified ezetimibe compound according to claim 1, comprising enhanced inhibition of HDM2 / HDM4-mediated suppression of p53 by the modified ezetimibe relative to unmodified ezetimibe.

3. The modified ezetimibe compound according to claim 1 or claim 2 having reduced glucuronidation in the intestine relative to unmodified ezetimibe.

4. The modified ezetimibe compound according to any one of claims 1 to 3, wherein the cancer is one in which there are elevated levels of HDM2, HDM4, or both HDM2 and HDM4 or where HDM2, HDM4, or both HDM2 and HDM4 is overexpressed.

5. The modified ezetimibe compound according to claim 4, wherein the cancer comprises colon cancer, colorectal cancer, sarcoma, glioma, lymphoma, breast cancer, lung cancer, liver cancer, esophagogastric cancer and gynaecological cancers.

6. The modified ezetimibe compound according to claim 4, wherein the cancer consists of colon cancer, colorectal cancer and esophagogastric cancer.

7. A pharmaceutical composition for oral administration comprising the modified ezetimibe compound as described in any one of claims 1 to 6, for use in the treatment of cancer.

8. A pharmaceutical composition according to claim 7, wherein the cancer comprises colon cancer, colorectal cancer, sarcoma, glioma, lymphoma, breast cancer, lung cancer, liver cancer, esophagogastric cancer and gynaecological cancer.

9. The pharmaceutical composition according to claim 8, wherein the cancer consists of colon cancer, colorectal cancer and esophagogastric cancer.

10. Use of the modified ezetimibe compound as described in any one of claims 1 to 6 in the manufacture of a medicament formulated for oral administration for the treatment of cancer.

11. The use of claim 10, wherein the cancer comprises colon cancer, colorectal cancer, sarcoma, glioma, lymphoma, breast cancer, lung cancer, liver cancer, esophagogastric cancer and gynaecological cancer.

12. The use of claim 11, wherein the cancer consists of colon cancer, colorectal cancer and esophagogastric cancer.

13. A method of treating cancer comprising the oral administration of the modified ezetimibe compound as described in any one of claims 1 to 6 to a subject in need thereof.

14. The method according to claim 13, wherein the cancer comprises colon cancer, colorectal cancer, sarcoma, glioma, lymphoma, breast cancer, lung cancer, liver cancer, esophagogastric cancer and gynaecological cancer.

15. The method according to claim 14, wherein the cancer consists of colon cancer, colorectal cancer and esophagogastric cancer.

16. The pharmaceutical composition according to any one of claims 7 to 9 or the use according to any one of claims 10 to 12 which is formulated as a tablet or capsule.

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