2,173
Views
0
CrossRef citations to date
0
Altmetric
Research Paper

Discovery of novel and potent dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment via structure-based pharmacophore modelling, virtual screening, and molecular docking, molecular dynamics simulation studies, and biological evaluation

, , , , &
Article: 2295241 | Received 29 Aug 2023, Accepted 11 Dec 2023, Published online: 22 Dec 2023

References

  • Khan N, Dhritlahre RK, Saneja A. Ruchika Recent advances in dual-ligand targeted nanocarriers for cancer therapy. Drug Discov Today. 2022;27(8):2288–2299.
  • Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.
  • Siegel RL, Wagle NS, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73(3):233–254.
  • Ciardiello F, Ciardiello D, Martini G, Napolitano S, Tabernero J, Cervantes A. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 2022;72(4):372–401.
  • Ren Y, Li S, Zhu R, Wan C, Song D, Zhu J, Cai G, Long S, Kong L, Yu W. Discovery of STAT3 and Histone Deacetylase (HDAC) dual-pathway inhibitors for the treatment of solid cancer. J Med Chem. 2021;64(11):7468–7482.
  • Navya PN, Kaphle A, Srinivas SP, Bhargava SK, Rotello VM, Daima HK. Current trends and challenges in cancer management and therapy using designer nanomaterials. Nano Converg. 2019;6(1):23.
  • Assaraf YG, Brozovic A, Gonçalves AC, Jurkovicova D, Linē A, Machuqueiro M, Saponara S, Sarmento-Ribeiro AB, Xavier CPR, Vasconcelos MH. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resist Updat. 2019;46:100645.
  • Sun D, Zhao Y, Zhang S, Zhang L, Liu B, Ouyang L. Dual-target kinase drug design: Current strategies and future directions in cancer therapy. Eur J Med Chem. 2020;188:112025.
  • Qin S, Jiang J, Lu Y, Nice EC, Huang C, Zhang J, He W. Emerging role of tumor cell plasticity in modifying therapeutic response. Signal Transduct Target Ther. 2020;5(1):228.
  • Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020;21(9):3233.
  • Ding S, Chen X, Shen K. Single-cell RNA sequencing in breast cancer: Understanding tumor heterogeneity and paving roads to individualized therapy. Cancer Commun. 2020;40(8):329–344.
  • Duan YC, Zhang SJ, Shi XJ, Jin LF, Yu T, Song Y, Guan YY. Research progress of dual inhibitors targeting crosstalk between histone epigenetic modulators for cancer therapy. Eur J Med Chem. 2021;222:113588.
  • Liang Q, Wang J, Zhao L, Hou J, Hu Y, Shi J. Recent advances of dual FGFR inhibitors as a novel therapy for cancer. Eur J Med Chem. 2021;214:113205.
  • Ye J, Wu J, Liu B. Therapeutic strategies of dual-target small molecules to overcome drug resistance in cancer therapy. Biochim Biophys Acta Rev Cancer. 2023;1878(3):188866.
  • Zou Y, Li W, Zhou J, Zhang J, Huang Y, Wang Z. ERK inhibitor enhances everolimus efficacy through the attenuation of dNTP pools in renal cell carcinoma. Mol Ther Nucleic Acids. 2019;14:550–561.
  • Ince W, Eisen T. Combination therapies in clinical trials for renal cell carcinoma: how could they impact future treatments? Expert Opin Investig Drugs. 2021;30(12):1221–1229.
  • Thakur A, Tawa GJ, Henderson MJ, Danchik C, Liu S, Shah P, Wang AQ, Dunn G, Kabir M, Padilha EC, et al. Design, synthesis, and biological evaluation of quinazolin-4-one-based hydroxamic acids as dual PI3K/HDAC inhibitors. J Med Chem. 2020;63(8):4256–4292.
  • O'Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, Prokop C, Espinosa R, 3rd, Le Beau MM, Earp HS, Liu ET. axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Cell Biol. 1991;11(10):5016–5031.
  • Antony J, Huang RY. AXL-driven EMT state as a targetable conduit in cancer. Cancer Res. 2017;77(14):3725–3732.
  • Myers SH, Brunton VG, Unciti-Broceta A. AXL inhibitors in cancer: a medicinal chemistry perspective. J Med Chem. 2016;59(8):3593–3608.
  • Tanaka M, Siemann DW. Therapeutic targeting of the Gas6/Axl signaling pathway in cancer. Int J Mol Sci. 2021;22(18):9953.
  • Wium M, Ajayi-Smith AF, Paccez JD, Zerbini LF. The role of the receptor tyrosine kinase Axl in carcinogenesis and development of therapeutic resistance: an overview of molecular mechanisms and future applications. Cancers. 2021; 13(7):1521.
  • Hsu CH, Huang YH, Lin SM, Hsu C. AXL and MET in hepatocellular carcinoma: a systematic literature review. Liver Cancer. 2022;11(2):94–112.
  • Cichoń MA, Szentpetery Z, Caley MP, Papadakis ES, Mackenzie IC, Brennan CH, O'Toole EA. The receptor tyrosine kinase Axl regulates cell-cell adhesion and stemness in cutaneous squamous cell carcinoma. Oncogene. 2014;33(32):4185–4192.
  • Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, Shen L, Fan Y, Giri U, Tumula PK, et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res. 2013;19(1):279–290.
  • Di Stasi R, De Rosa L, D'Andrea LD. Therapeutic aspects of the Axl/Gas6 molecular system. Drug Discov Today. 2020;25(12):2130–2148.
  • Wu G, Ma Z, Cheng Y, Hu W, Deng C, Jiang S, Li T, Chen F, Yang Y. Targeting Gas6/TAM in cancer cells and tumor microenvironment. Mol Cancer. 2018;17(1):20.
  • Zhu C, Wei Y, Wei X. AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol Cancer. 2019;18(1):153.
  • Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer. 2014;14(12):769–785.
  • Tanaka M, Siemann DW. Gas6/Axl signaling pathway in the tumor immune microenvironment. Cancers. 2020;12(7):1850.
  • Gao X, Xue D, Cheng J, Zhang X, Cai X. Inhibition of Axl promotes the therapeutic effect of targeted inhibition of the PI3K/Akt pathway in NRAS mutant melanoma cells. J Oncol. 2022;2022:2946929–2946929.
  • Hafizi S, Dahlbäck B. Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine Growth Factor Rev. 2006;17(4):295–304.
  • Lauter M, Weber A, Torka R. Targeting of the AXL receptor tyrosine kinase by small molecule inhibitor leads to AXL cell surface accumulation by impairing the ubiquitin-dependent receptor degradation. Cell Commun Signal. 2019;17(1):59.
  • Bhalla S, Gerber DE. AXL inhibitors: status of clinical development. Curr Oncol Rep. 2023;25(5):521–529.
  • Jeon JY, Buelow DR, Garrison DA, Niu M, Eisenmann ED, Huang KM, Zavorka Thomas ME, Weber RH, Whatcott CJ, Warner SL, et al. TP-0903 is active in models of drug-resistant acute myeloid leukemia. JCI Insight. 2020;5(23):e140169.
  • Ben-Batalla I, Erdmann R, Jørgensen H, Mitchell R, Ernst T, von Amsberg G, Schafhausen P, Velthaus JL, Rankin S, Clark RE, et al. Axl blockade by BGB324 inhibits BCR-ABL tyrosine kinase inhibitor-sensitive and -resistant chronic myeloid leukemia. Clin Cancer Res. 2017;23(9):2289–2300.
  • Kasikara C, Davra V, Calianese D, Geng K, Spires TE, Quigley M, Wichroski M, Sriram G, Suarez-Lopez L, Yaffe MB, et al. Pan-TAM tyrosine kinase inhibitor BMS-777607 enhances anti-PD-1 mAb efficacy in a murine model of triple-negative breast cancer. Cancer Res. 2019;79(10):2669–2683.
  • Rho JK, Choi YJ, Kim SY, Kim TW, Choi EK, Yoon SJ, Park BM, Park E, Bae JH, Choi CM, et al. MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to EGFR kinase inhibitors because of MET or AXL activation. Cancer Res. 2014;74(1):253–262.
  • Brand TM, Iida M, Stein AP, Corrigan KL, Braverman CM, Coan JP, Pearson HE, Bahrar H, Fowler TL, Bednarz BP, et al. AXL is a logical molecular target in head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(11):2601–2612.
  • Tian Y, Zhang Z, Miao L, Yang Z, Yang J, Wang Y, Qian D, Cai H, Wang Y. Anexelekto (AXL) increases resistance to EGFR-TKI and activation of AKT and ERK1/2 in non-small cell lung cancer cells. Oncol Res. 2016;24(5):295–303.
  • Kim KC, Baek SH, Lee C. Curcumin-induced downregulation of Axl receptor tyrosine kinase inhibits cell proliferation and circumvents chemoresistance in non-small lung cancer cells. Int J Oncol. 2015;47(6):2296–2303.
  • Sanchez GJ, Richmond PA, Bunker EN, Karman SS, Azofeifa J, Garnett AT, Xu Q, Wheeler GE, Toomey CM, Zhang Q, et al. Genome-wide dose-dependent inhibition of histone deacetylases studies reveal their roles in enhancer remodeling and suppression of oncogenic super-enhancers. Nucleic Acids Res. 2018;46(4):1756–1776.
  • Ferrante F, Giaimo BD, Bartkuhn M, Zimmermann T, Close V, Mertens D, Nist A, Stiewe T, Meier-Soelch J, Kracht M, et al. HDAC3 functions as a positive regulator in Notch signal transduction. Nucleic Acids Res. 2020;48(7):3496–3512.
  • Peng X, Sun Z, Kuang P, Chen J. Recent progress on HDAC inhibitors with dual targeting capabilities for cancer treatment. Eur J Med Chem. 2020;208:112831.
  • Jia D, Augert A, Kim DW, Eastwood E, Wu N, Ibrahim AH, Kim KB, Dunn CT, Pillai SPS, Gazdar AF, et al. Crebbp loss drives small cell lung cancer and increases sensitivity to HDAC inhibition. Cancer Discov. 2018;8(11):1422–1437.
  • Zhang L, Han Y, Jiang Q, Wang C, Chen X, Li X, Xu F, Jiang Y, Wang Q, Xu W. Trend of histone deacetylase inhibitors in cancer therapy: isoform selectivity or multitargeted strategy. Med Res Rev. 2015;35(1):63–84.
  • Hu XT, Xing W, Zhao RS, Tan Y, Wu XF, Ao LQ, Li Z, Yao MW, Yuan M, Guo W, et al. HDAC2 inhibits EMT-mediated cancer metastasis by downregulating the long noncoding RNA H19 in colorectal cancer. J Exp Clin Cancer Res. 2020;39(1):270.
  • Shetty MG, Pai P, Deaver RE, Satyamoorthy K, Babitha KS. Histone deacetylase 2 selective inhibitors: a versatile therapeutic strategy as next generation drug target in cancer therapy. Pharmacol Res. 2021;170:105695.
  • Wan G, Feng Z, Zhang Q, Li X, Ran K, Feng H, Luo T, Zhou S, Su C, Wei W, et al. Design and synthesis of fibroblast growth factor receptor (FGFR) and histone deacetylase (HDAC) dual inhibitors for the treatment of cancer. J Med Chem. 2022;65(24):16541–16569.
  • Lee HZ, Kwitkowski VE, Del Valle PL, Ricci MS, Saber H, Habtemariam BA, Bullock J, Bloomquist E, Li Shen Y, Chen XH, et al. FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clin Cancer Res. 2015;21(12):2666–2670.
  • Suraweera A, O'Byrne KJ, Richard DJ. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: achieving the full therapeutic potential of HDACi. Front Oncol. 2018;8:92.
  • Leszczynska KB, Jayaprakash C, Kaminska B, Mieczkowski J. Emerging advances in combinatorial treatments of epigenetically altered pediatric high-grade H3K27M gliomas. Front Genet. 2021;12:742561.
  • Meel MH, de Gooijer MC, Metselaar DS, Sewing ACP, Zwaan K, Waranecki P, Breur M, Buil LCM, Lagerweij T, Wedekind LE, et al. Combined therapy of AXL and HDAC inhibition reverses mesenchymal transition in diffuse intrinsic pontine glioma. Clin Cancer Res. 2020;26(13):3319–3332.
  • Wang SC, Yu CY, Wu YC, Chang YC, Chen SL, Sung WW. Chidamide and mitomycin C exert synergistic cytotoxic effects against bladder cancer cells in vitro and suppress tumor growth in a rat bladder cancer model. Cancer Lett. 2022;530:8–15.
  • Wang J, Pursell NW, Samson ME, Atoyan R, Ma AW, Selmi A, Xu W, Cai X, Voi M, Savagner P, et al. Potential advantages of CUDC-101, a multitargeted HDAC, EGFR, and HER2 inhibitor, in treating drug resistance and preventing cancer cell migration and invasion. Mol Cancer Ther. 2013;12(6):925–936.
  • Zheng L, Ren R, Sun X, Zou Y, Shi Y, Di B, Niu MM. Discovery of a dual tubulin and poly(ADP-Ribose) polymerase-1 inhibitor by structure-based pharmacophore modeling, virtual screening, molecular docking, and biological evaluation. J Med Chem. 2021;64(21):15702–15715.
  • Zhou Y, Chen Y, Tan Y, Hu R, Niu MM. An NRP1/MDM2-targeted D-peptide supramolecular nanomedicine for high-efficacy and low-toxic liver cancer therapy. Adv Healthc Mater. 2021;10(9):e2002197.
  • Winitthana T, Lawanprasert S, Chanvorachote P. Triclosan potentiates epithelial-to-mesenchymal transition in Anoikis-resistant human lung cancer cells. PLOS One. 2014;9(10):e110851.
  • Zhou Y, Tang S, Chen T, Niu MM. Structure-based pharmacophore modeling, virtual screening, molecular docking and biological evaluation for identification of potential poly (ADP-Ribose) polymerase-1 (PARP-1) inhibitors. Molecules. 2019;24(23):4258.
  • Li X, Inks ES, Li X, Hou J, Chou CJ, Zhang J, Jiang Y, Zhang Y, Xu W. Discovery of the first N-hydroxycinnamamide-based histone deacetylase 1/3 dual inhibitors with potent oral antitumor activity. J Med Chem. 2014;57(8):3324–3341.
  • Ng PS, Foo K, Sim S, Wang G, Huang C, Tan LH, Poulsen A, Liu B, Tee DHY, Ahmad NHB, et al. Fragment-based lead discovery of indazole-based compounds as AXL kinase inhibitors. Bioorg Med Chem. 2021;49:116437.
  • Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, Lindahl E. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1-2:19–25.
  • Páll S, Zhmurov A, Bauer P, Abraham M, Lundborg M, Gray A, Hess B, Lindahl E. Heterogeneous parallelization and acceleration of molecular dynamics simulations in GROMACS. J Chem Phys. 2020;153(13):134110.
  • Zhou Y, Zou Y, Yang M, Mei S, Liu X, Han H, Zhang CD, Niu MM. Highly potent, selective, biostable, and cell-permeable cyclic d-peptide for dual-targeting therapy of lung cancer. J Am Chem Soc. 2022;144(16):7117–7128.
  • Noh JH, Bae HJ, Eun JW, Shen Q, Park SJ, Kim HS, Nam B, Shin WC, Lee EK, Lee K, et al. HDAC2 provides a critical support to malignant progression of hepatocellular carcinoma through feedback control of mTORC1 and AKT. Cancer Res. 2014;74(6):1728–1738.
  • Ma S, Liu T, Xu L, Wang Y, Zhou J, Huang T, Li P, Liu H, Zhang Y, Zhou X, et al. Histone deacetylases inhibitor MS-275 suppresses human esophageal squamous cell carcinoma cell growth and progression via the PI3K/Akt/mTOR pathway. J Cell Physiol. 2019;234(12):22400–22410.
  • Sun J, Piao J, Li N, Yang Y, Kim KY, Lin Z. Valproic acid targets HDAC1/2 and HDAC1/PTEN/Akt signalling to inhibit cell proliferation via the induction of autophagy in gastric cancer. Febs J. 2020;287(10):2118–2133.
  • Adam-Artigues A, Arenas EJ, Martínez-Sabadell A, Brasó-Maristany F, Cervera R, Tormo E, Hernando C, Martínez MT, Carbonell-Asins J, Simón S, et al. Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer. Sci Adv. 2022;8(20):eabk2746.