Photoswitchable compounds modulating cadherin homodimerization

Abstract

Invention relates to photoswitchable azobenzene-based compounds, particularly to azobenzene-based compounds that allows light-triggered modulation of the cell-cell adhesion family of proteins called cadherins and their use in the treatment of cancer and other diseases. We have discovered photoswitchable compounds that are active at < 100 μM concentration on BxPC-3 cells expressing E-cadherin and P-cadherin. These novel compounds can be used for manufacturing of various pharmaceutical compositions, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers or excipients.

Description

Photoswitchable compounds modulating cadherin homodimerizationFIELD OF THE INVENTION

[0001] Invention relates to photoswitchable azobenzene-based compounds, particularly to azobenzene-based compounds that allows light-triggered modulation of the cell-cell adhesion family of proteins called cadherins and their use in the treatment of cancer and other diseases.BACKGROUND OF THE ART

[0002] Photopharmacology is based on the concept that, since the pharmacodynamics and pharmacokinetic properties of drugs are directly related to their molecular structure, the photoinduced structural change of photoswitchable drugs allows the activation / deactivation or modulation of their biological functions only in the region where light is provided.1Hence, it is expected that photopharmacology will greatly contribute to drug discovery in the years to come. However, while it has been clearly demonstrated that photopharmacology can be used to modulate cellular and sub-cellular events in a spatio-temporally-controlled way2, the therapeutic and diagnostic potential of this approach is currently still far from being fully exploited, particularly with respect to the modulation of protein-protein interactions (PPIs).

[0003] The notion that proteins rarely work alone inside the cell but rather they usually function in association with other proteins in the form of multi-protein complexes has led to the identification of selected PPIs as bona fide therapeutic targets. For instance, PPIs are involved, inter alia, in metabolic reactions, in membrane transport mechanisms, in signal transduction events within cells and in muscle contraction at the macroscale.3

[0004] When PPIs are the target, specificity and selectivity are hard to achieve by conventional drug design methods. Within this scope, the idea to use light as an external stimulus to modulate or even inhibit PPIs (or even single protein targets) is at the core of the field of photopharmacology. Cell-cell adhesion, which is the process that leads to tissue formation, is mediated by a number of PPIs involving different type of cell adhesion proteins, such as for instance cadherins. Cadherins are a class of calcium-dependent cell adhesion molecules that localize at the intercellular junctions and play a crucial role in tissue morphogenesis and architectural integrity.4,5It has been clearly shown that aberrant expression of epithelial E-cadherin (CDH1) and neuronal N-cadherin (CDH2) often correlates with tumor progression.6 8

[0005] Indeed, the switch in expression from E- to N-cadherin is a key event in the cellular epithelial-to-mesenchymal transition (EMT) that takes place as cancer progresses. Despite its tumor repressor role in the majority of carcinomas, in epithelial ovarian cancer (EOC) cells E- cadherin shows a high level of expression during tumor progression and facilitates EOC cell proliferation.9

[0006] Interestingly, most cadherin-family members are now considered potential pharmaceutical targets in a variety of clinical settings.In 2016, we reported the crystal structure of the complex between a human E-cadherin extracellular fragment and the peptidomimetic inhibitor FR159 (PDB code: 4ZTE).10This structure allowed the identification of a druggable interface and provided clear evidence of a possible mechanism of modulation of cadherin dimerization. Based on this novel and unique crystal structure, we conducted a virtual screening (VS) analysis and further identified other compounds that inhibit E- cadherin dimerization with good potency (pM range) and specificity.11While an optogenic approach designed to optically control the activation of a cadherin protein via genetic modifications of the protein has been described in the literature12 13, photopharmacological approaches to cadherin modulation have never been reported.

[0007] Ritterson et al.12reported the photocontrol of cadherin-mediated cell-cell adhesion via the modulation of the protein’s calcium-binding affinity, which affects cadherin homodimerization. Since Ca2+is essential for cadherin activity, the photocontrol of the calcium binding affinity was shown to produce a modulation of the cadherin adhesive properities. To do so, the authors mutated two specific amino acids into cysteines and made these cysteines react with an azobenze compound bearing 2-chloroacetamido substituents, which allowed its conjugation with the cysteins.

[0008] In 2020, Ollech et al.14published an optochemical tool to induce light-triggered dissociation of cellular adherens junctions. Their photocleavage-based tool is active on the intracellular E- cadherin- 0-catenin complex at the adherens juntions.

[0009] In 2023 study by Mombo et al. was published on the Opto-E-cadherin tool.13The Opto-E- cadherin tool allows reversible control of E-cadherin-mediated cell-cell adhesion with blue light. This optogenetic tool has been designed by engineering the calcium binding site in E-cadherin, allowing calcium complexation to be modulated by light. The authors focused on the calcium- binding site between the first (ECI) and the second (EC2) extracellular domain, which are involved in cadherin homodimerization, hence in the cell-cell adhesion mechanism. The geneticmodification consists in the introduction of the L0V2 domain of Avena sativa phototropin 1 (AsL0V2) before a connecting loop in the E-cadherin structure.

[0010] Photoswitchable drugs, which can be "activated" or "deactivated" by light, provide the possibility to modulate a protein target reversibly. This is an advantage over photocaged compounds. Photocaged compounds are photosensitive molecules where a drug is covalently bound to a photocl eavable group that hinder the drug action. By exposure to a proper light stimulus, the photocleavable part is removed and the drug is free to interact with the receptor. As a drawback, the action of photocaged drugs is irreversible since the photocleaved reaction cannot be reverted. In our invention, we use the azobenzene chemical moiety as the photoswitchable unit.[Oi l] Azobenzenes are small molecules which can be switched reversibly between two different isomers (trans and cis) by exposure to light of specific wavelength. In the trans configuration the compound is stable at room temperature; by absorption of UV or visible light, the compound is converted to a metastable cis configuration. This isomerization involves the rotation of the aromatic ring on the same side of the azo (-N=N-) bond. As this conformational change causes steric hindrance, cis -azobenzene tends to undergo thermal isomerization to return to the more stable trans-azobenzene configuration. The conversion from cis- to trans- azobenzene can be obtained also photochemically by illumination with a light of wavelength in the visible region (usually between 400-600 nm). These properties allow the reversible photocontrol of the configuration of the molecule and the modulation of the biological activity of the target protein1 15 16while the action of conventional drugs is usualy not associated with spatio-temporal precision, photoswitchable drugs can be activated and deactivated where and when needed. Therefore, there is a need to develop photopharmacology approaches to the modulation of important pharmacological targets such as cell-cell adhesion proteins.

[0012] In 2022 Mari et al. developed a light-responsive azobenzene film as a cell culturing platform. Upon photoconversion, the azobenzene film generates a surface relief grating (SRG) that guides cell orientation. This system is proposed as a reconfigurable cell culture platform for dynamically controlling cell-material interactions18. In contrast, our invention introduces a series of compounds that can be applied as a solution to a cell culture, enabling photocontrol of cell-cell interaction. Unlike the referenced study, which employs a stimuli-responsive material to mechanically influence cell adhesion and orientation through a surface patterning, our approach targets specific pharmacological pathways involving E-cadherin and P-cadherin proteins.

[0013] In 2016 J.E.Sheldon et al. developed a photoswitchable analog of comberstatin A-4 (Azo- CA4), which functions as an inhibitor of tubulin polymerization. In its illuminated form, this compound exhibits toxicity and demonstrates antitumor activity19. In contrast, our invention has a different scope and a different pharmacological target (E-cadherin and P-cadherin proteins) and a therefore a different mechanism of action. Unlike Azo-CA4, our approach does not inhibit tubulin polymerization or induce cell death. Instead, it modulates cadherin-mediated cell-cell adhesion without eliciting cytotoxic effects.

[0014] The present invention relates to the development of photoswitchable molecules that are capable of modulating E-cadherin homodimerization, i.e. the process that mediates adherens junction formation and allows cell-cell adhesion.

[0015] Our molecular design is based on the AS8 compound previously identified by the Parisini group11as a modulator of E-cadherin homodimerization.

[0016] For our design, we followed an azologization approach whereby we performed a bioisosteric substitution of sulfonamide or amide groups with an azobenzene moiety. This design allowed the introduction of the smallest possible chemical perturbation to the starting compound.17THE PRESENT INVENTION

[0017] We have discovered photoswitchable compounds that are active at < 100 pM concentration on BxPC-3 cells expressing E-cadherin and P-cadherin. These novel compounds can be used for manufacturing of various pharmaceutical compositions, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers or excipients.SUMMARY OF THE INVENTION

[0018] We disclose compounds selected from those of Formula (I)I wherein:X and Y are independently a substituted or unsubstituted aryl ring, wherein at least one of the ring is substituted with one or more cadherin-binding moieties. X and Y can be in some cases equal.

[0019] In some embodiments, a compound of Formula (I) is a compound of Formula (II):n wherein:R1 is independently selected from the group consisting of: hydrogen, N- phenylmethanesulfonamide, N-(m-tolyl)methanesulfonamide, N-phenylacetamide;R2 is independently selected from the group consisting of: hydrogen, N- phenylmethanesulfonamide, N-(m-tolyl)methanesulfonamide, N-phenylacetamide;In some embodiments Ri and R2 are in the meta position.In some embodiments Ri and R2 are in the para position.

[0020] We also disclose a method for modulating cadherin-mediated cell-cell adhesion in a cell population comprising steps of: a) providing a cell population; b) contacting the cell population of step (a) with an effective amount of a compound of Formula (I) either in its dark-adapted form or in its pre-illuminated form, wherein in the pre-illuminated form the compound has been exposed for at least 10 min to UV light.

[0021] The term “aryl ring” refers to benzyl or phenyl groups, substituted or unsubstituted.The term “cadherin-binding moieties” refers to portions of the molecule that establish stabilizing contacts (such as van der Waals or hydrogen bonding or electrostatic interactions) with the cadherin protein.The term “effective amount” refers to the amount of a compound provided herein that is sufficient to achieve the desired effect of modulating cadherin-mediated cell-cell adhesion.The term “contacting” refers to forming stabilizing contacts (van der Waals, hydrogen bonding or electrostatic) with the cadherin protein.The term “dark-adapted” refers to the compound that has been shielded from light for a sufficient period (the duration of this period of time may vary significantly depending on the compound, however it is typically in the range of 0-10 hours), allowing it to assume its baseline condition.The term “pre-illuminated” refers to a compound that has been exposed to light for a predetermined period (the duration of this period of time may vary significantly depending on the compound, however it is typically in the range of 1-60 minutes) before its application in the well with cells.The term “cell population” refers to a population of cadherin-expressing cells.

[0022] Specific compounds of Formula I within the present invention include but are not limited to:

[0023] Description of drawingsFIG 1 - A) The photoswitchable reaction from cis to trans can be address with visible light or spontaneously by UV light. The trans to cis reaction can be obtained by UV illumination. B-D) HPLC chromatogram of a photoswitchable compound of Formula I: Chromatogram obtained under benchtop conditions (B); Chromatogram obtained after 10 minutes of irradiation at 365 nm (6W lamp) (C); Chromatogram obtained after 4 h of relaxation at 37°C (D). The percentage of trans and cis compounds can be obtained from the integration of the peak at 3.7 min (trans) and 3.1 min (cis) of retention time.FIG 2 - Optical images of cellular spheroids of human pancreatic tumor BxPC-3 cells. Scale bar: 1000 pm A-C) Cellular spheroids after addition of compound 4 (100 pM, 75 pM, 50 pM) in thedark-adapted or in the pre-illuminated form (50 min, 365 nm, 6W) after 24h incubation. D) Cellular spheroids after addition of compound 14 (50pM) in the dark-adapted or in the preilluminated form (50 min, 365 nm, 6W) after 24h incubation. E) Control experiments: cellular spheroids after addition of 50 pM DMSO stored in the dark and after pre-illumination (50 min, 365 nm, 6W) after 24h incubation.FIG 2A shows the control experiment with DMSO (50 pM, 2 %) where BxPC-3 cells aggregate in spheroids either after addition of DMSO kept in dark or pre-illuminated as of the testing compound. Therefore, without an inhibition cadherin expressed on the cell surface drive the clustering of the cells.FIG 2B shows the inhibition effect of compound 14, at 50 pM the molecule stored in dark (trans) partially inhibit the cell adhesion, while the inhibition is higher after the application of the preilluminated compound (cis).FIG 2C, FIG 2D, FIG 2E a dose response is shown for compound 4, where at 100 pM both dark- adapted (trans) and pre-illuminated (cis) compound strongly inhibit the cell-cell adhesion. At 75 pM the inhibition effect is stronger for the dark-adapted (trans) compound than for the preilluminated (cis) compound, at 50 pM also the effect of dark-adapted (trans) compound is moderate and the effect of the pre-illuminated (cis) compound is almost negligible.

[0024] Examples of specific embodimentsThe following examples further illustrate the invention, but should not be construed to limit the scope of the invention in any way.General scheme for compounds of Formula II:IIAll compounds were prepared via a convergent synthetic route. Reagent II was obtained by oxidation of its amine precursor (reagent I) with Oxone in a biphasic system of dichloromethane and water as reported in scheme I.The final compounds were obtained by Mills coupling conditions between nitrose and amine as reported in Scheme II and Scheme III.

[0025] Scheme 1 describes the preparation reagent II of the present invention.Scheme 1Reagents and conditions: (a) 3-amino-N-phenylbenzenesulfonamide, Oxone, H2O:DCM 3:1.

[0026] Scheme 2 describes the preparation of compound 13 of the present invention.Scheme 2Reagents and conditions: (b) 3-amino-N-phenylbenzenesulfonamide, 3-nitroso-N- phenylbenzenesulfonamide, acetic acid, room temperature.

[0027] Scheme 3 describes the preparation of compound 8 of the present invention.Scheme 38Reagents and conditions: (c) 3-amino-N-phenylbenzamide, nitrosobenzene, acetic acid, room temperature

[0028] Synthesis of N-phenyl-3-(phenyldiazenyl)benzamide (8):To a solution of 3-amino-N-phenylbenzamide (0.1 g, 0.47 mmol) in 13 ml of acetic acid, nitrosobenzene (75.70 mg, 0.7 mmol) dissolved in 10 ml of acetic acid was added dropwise undernitrogen. The reaction was stirred at room temperature under nitrogen for 24 h. Most of the solvent was evaporated under reduced pressure. The remaining solvent was diluted with EtOAc and extracted from water. The organic layer was rinsed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give a crude mixture of 89 mg. The crude mixture was then purified by column chromatography using a direct phase column and a mixture of hexane: ethyl acetate (76:24) to give the final product (0.068 g, 37 % yield).1H NMR (400 MHz, DMSO) 8 10.26 (s, 1H), 8.21 (s, 1H), 7.95 - 7.82 (m, 2H), 7.71 (dd, 2H), 7.53 (dd, 3H), 7.38 (q, 3H), 7.18 - 7.08 (m, 2H), 6.90 (t, 1H).13C NMR (400 MHz, DMSO) 8 165.11, 152.06, 152.01, 139.09, 136.43, 132.19, 130.70, 130.01, 129.83, 128.93, 125.56, 124.24, 122.92, 121.89, 120.79.Crystal Data for C19H15N3O (8) (M = 301.35 g / mol): monoclinic, space group Pc (no. 7), a = 12.9243(3) A, b = 4.9091(1) A, c = 11.6280(2) A, 0 = 91.870(2)°, V= 737.37(3) A3, Z = 2, T = 140.0(1) K, p(Cu Ka) = 0.689 mm'1, Dcalc = 1.3572 g / cm3, 5738 reflections measured (20 < 160°), 2203 unique ( / 8 m = 0.0262, / / sigma = 0.0318) which were used in all calculations. The final / ?i was 0.0393 (I > 2a(T)) and wRz was 0.1059 (all data).

[0029] Synthesis of 3-nitroso-N-phenylbenzenesulfonamide (12):To a solution of 3-amino-N-phenylbenzenesulfonamide (0.2 g, 0.80 mmol) dissolved in 24 ml of DCM was added a solution of oxone (0.494 mg, 1.6 mmol) in 72 ml of water and stirred under nitrogen.The reaction is monitored by TLC, and after 4h was extracted with DCM and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 650 mg crude. The crude was purified with flash chromatography using a mixture of hexane:ethyl acetate (6:94) to obtain a blue nitroso product (0.05 g, 24 % yield). The product was used in the following reaction without further characterization and purification steps.

[0030] Synthesis of 3,3'-(diazene-l^-diyl)bis(N-phenylbenzenesulfonamide) (13):To a solution of 3-amino-N-phenylbenzenesulfonamide (0.032 g, 0.122 mmol) dissolved in 5 ml of acetic acid was added a solution of 3-nitroso-N-phenylbenzenesulfonamide (0.050 g, 0.20 mmol) in 6 ml of acetic acid and stirred under nitrogen. The reaction was monitored by TLC, and after 48h the acetic acid was almost completely evaporated under reduced pressure and then thereaction was extracted with ethyl acetate and bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The crude was purified with flash chromatography using a mixture of hexane:ethyl acetate (2:8) to obtain the final product (0.027 g, 35 % yield).'H NMR (400 MHz, DMSO) 8 10.30 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 8.00-7.94 (m, 1H), 7.76 (dt, J=7.9, 1.5 Hz, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.09-7.03 (m, 2H), 6.93 (d, J=7.6 Hz, 2H), 6.87 (t, J=7.4 Hz, 1H).13C NMR (400 MHz, DMSO) 8 151.19, 141.15, 137.45, 131.12, 129.82, 129.47, 128.24, 124.75, 120.79, 119.62.Crystal Data for C24H20N4O4S2 (13) (M = 492.56 g / mol): monoclinic, space group P21 / c (no.14), a = 18.205(2) A, b = 4.9755(3) A, c = 12.349(1) A, 0 = 91.693(9)°, V = 1118.1(2) A3, Z = 2, T = 150.0(1) K, p(CuKa) = 2.508 mm-1, Deale = 1.463 g / cm3, 9876 reflections measured (20 < 160.0°), 2391 unique (Rint = 0.0699, Rsigma = 0.0564) which were used in all calculations. The final R1 was 0.0631 (I > 2o(I)) and wR2 was 0.1861 (all data).References(1) Hull, K.; Morstein, J.; Trauner, D. In Vivo Photopharmacology. Chem. Rev. 2018, 118 (21), 10710-10747. https: / / doi.org / 10.1021 / acs.chemrev.8b00037.(2) Cabre, G.; Garrido-Charles, A.; Moreno, M.; Bosch, M.; Porta-de-la-Riva, M.; Krieg, M.; Gasc6n-Moya, M.; Camarero, N.; Gelabert, R.; Lluch, J. M.; Busque, F.; Hernando, J.; Gorostiza, P.; Alibes, R. Rationally Designed Azobenzene Photoswitches for Efficient Two -Photon Neuronal Excitation. Nat. Commun. 2019, 10 (1), 907. https: / / doi.org / 10.1038 / s41467-019-08796-9.(3) Mabonga, L.; Kappo, A. P. Protein-Protein Interaction Modulators: Advances, Successes and Remaining Challenges. Biophys. Rev. 2019, 11 (4), 559-581. https: / / d01.0rg / l 0.1007 / sl 2551 -019-00570-x.(4) Gumbiner, B. M. Regulation of Cadherin-Mediated Adhesion in Morphogenesis. Nat. Rev. Mol. Cell Biol. 2005, 6 (8), 622-634. https: / / doi.org / 10.1038 / nrml699.(5) Leckband, D.; Sivasankar, S. Cadherin Recognition and Adhesion. Curr. Opin. Cell Biol. 2012, 24 (5), 620-627. https: / / doi.Org / 10.1016 / j.ceb.2012.05.014.(6) Blaschuk, O. W.; Devemy, E. Cadherins as Novel Targets for Anti-Cancer Therapy. Eur.J. Pharmacol. 2009, 625 (1-3), 195-198. https: / / doi.Org / 10.1016 / j.ejphar.2009.05.033.(7) Berx, G.; van Roy, F. Involvement of Members of the Cadherin Superfamily in Cancer. Cold Spring Harb. Perspect. Biol. 2009, 1 (6). https: / / doi.Org / 10.l 101 / cshperspect.a003129.(8) Zhao, H.; Hu, H.; Chen, B.; Xu, W.; Zhao, J.; Huang, C.; Xing, Y.; Lv, H.; Nie, C.; Wang, J.; He, Y.; Wang, S. Q.; Chen, X. B. Overview on the Role of E-Cadherin in Gastric Cancer: Dysregulation and Clinical Implications. Front. Mol. Biosci. 2021, 8 (July), 1-11. https: / / doi.org / 10.3389 / fmolb.2021.689139.(9) De Santis, G; Miotti, S.; Mazzi, M.; Canevari, S.; Tomassetti, A. E-Cadherin Directly Contributes to PI3K / AKT Activation by Engaging the PI3K-P85 Regulatory Subunit to Adherens Junctions of Ovarian Carcinoma Cells. 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Orthogonal Control of Neuronal Circuits and Behavior Using Photopharmacology. J. Mol. Neurosci. 2022, 72, 1433-1442. https : / / doi.org / l 0.1007 / s 12031 -022-02037-3.(17) Kobauri, P.; Szymanski, W.; Cao, F.; Thallmair, S.; Marrink, S. J.; Witte, M. D.; Dekker, F. J.; Feringa, B. L. Biaryl Sulfonamides as: Cisoid Azosteres for Photopharmacology. Chem. Commun. 2021, 57 (34), 4126-4129. https: / / doi.org / 10.1039 / dlcc00950h.(18) Isomaki, M.; Fedele, Ch.; Kaariainen, L.; Mantyla, E.; Nymark, S.; Ihalainen, O T.; Priimagi, A. Light-Responsive bilayer cell culture platform for reversible cell guidance. Small Science . 2022, 2, 2100099. https: / / onlinelibrary. wiley. com / doi / pdfdirect / 10.1002 / smsc.202100099(19) Sheldon, E.J.; Dcona, M.M; Lyons, E.Ch.; Hackett C.J.; Hartman, T.C.M. Photoswitchable anticancer activity via trans-cis isomerization of a combretastatin A-4 analog. 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Claims

Claims1. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:R1 is independently selected from the group consisting of: hydrogen, N- phenylmethanesulfonamide, N-(m-tolyl)methanesulfonamide, N- phenylacetamide;R2 is independently selected from the group consisting of: hydrogen, N- phenylmethanesulfonamide, N-(m-tolyl)methanesulfonamide, N- phenylacetamide.

2. The compound according to Claim 1 wherein R1 and R2 are in the meta position.

3. The compound according to Claim 1 wherein R1 and R2 are in the para position.

4. A method for modulating cadherin-mediated cell-cell adhesion in a cell population comprising steps of: a) providing a cell population; b) contacting the cell population of step (a) with an effective amount of a compound of Formula (II) according to Claim 1 either in its: dark-adapted form where the compound is shielded from light for 0-10 h; or pre-illuminated form where the compound is exposed to light for 1-60 min, wherein in the pre-illuminated form the compound has been exposed for at least 10 min to UV light.

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