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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

In silico Exploration of a Novel ICMT Inhibitor with More Solubility than Cysmethynil against Membrane Localization of KRAS Mutant in Colorectal Cancer

Author(s): Mohammed Mouhcine*, Youness Kadil, Ibtihal Segmani, Imane Rahmoune and Houda Filali

Volume 20, Issue 7, 2024

Published on: 03 June, 2024

Page: [1055 - 1069] Pages: 15

DOI: 10.2174/0115734099264451231003172217

Price: $65

Abstract

Background: ICMT (isoprenylcysteine carboxyl methyltransferase) is an enzyme that plays a key role in the post-translational modification of the K-Ras protein. The carboxyl methylation of this protein by ICMT is important for its proper localization and function. Cysmethynil (2-[5-(3-methylphenyl)-l-octyl-lH-indolo-3-yl] acetamide) causes K-Ras mislocalization and interrupts pathways that control cancer cell growth and division through inhibition of ICMT, but its poor water solubility makes it difficult and impractical for clinical use. This indicates that relatively high amounts of cysmethynil would be required to achieve an effective dose, which could result in significant adverse effects in patients.

Objective: The general objective of this work was to find virtually new compounds that present high solubility in water and are similar to the pharmacological activity of cysmethynil.

Materials and Methods: Pharmacophore modeling, pharmacophore-based virtual screening, prediction of ADMET properties (absorption, distribution, metabolism, excretion, and toxicity), and water solubility were performed to recover a water-soluble molecule that shares the same chemical characteristics as cysmethynil using Discovery Studio v16.1.0 (DS16.1), SwissADME server, and pkCSM server.

Results: In this study, ten pharmacophore model hypotheses were generated by exploiting the characteristics of cysmethynil. The pharmacophore model validated by the set test method was used to screen the "Elite Library®" and "Synergy Library" databases of Asinex. Only 1533 compounds corresponding to all the characteristics of the pharmacophore were retained. Then, the aqueous solubility in water at 25°C of these 1533 compounds was predicted by the Cheng and Merz model. Among these 1533 compounds, two had the optimal water solubility. Finally, the ADMET properties and Log S water solubility by three models (ESOL, Ali, and SILICOS-IT) of the two compounds and cysmethynil were compared, resulting in compound 2 as a potential inhibitor of ICMT.

Conclusion: According to the results obtained, the identified compound presented a high solubility in water and could be similar to the pharmacological activity of cysmethynil.

« Previous Next »
[1]
Sexton, R.E.; Mpilla, G.; Kim, S.; Philip, P.A.; Azmi, A.S. Ras and exosome signaling. Semin. Cancer Biol., 2019, 54, 131-137.
[http://dx.doi.org/10.1016/j.semcancer.2019.02.004] [PMID: 30769101]
[2]
Ostrem, J.M.; Peters, U.; Sos, M.L.; Wells, J.A.; Shokat, K.M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 2013, 503(7477), 548-551.
[http://dx.doi.org/10.1038/nature12796] [PMID: 24256730]
[3]
Ternet, C.; Kiel, C. Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage. Cell Commun. Signal., 2021, 19(1), 31.
[http://dx.doi.org/10.1186/s12964-021-00712-3] [PMID: 33691728]
[4]
Di Nicolantonio, F.; Arena, S.; Tabernero, J.; Grosso, S.; Molinari, F.; Macarulla, T.; Russo, M.; Cancelliere, C.; Zecchin, D.; Mazzucchelli, L.; Sasazuki, T.; Shirasawa, S.; Geuna, M.; Frattini, M.; Baselga, J.; Gallicchio, M.; Biffo, S.; Bardelli, A. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J. Clin. Invest., 2010, 120(8), 2858-2866.
[http://dx.doi.org/10.1172/JCI37539] [PMID: 20664172]
[5]
Nussinov, R.; Tsai, C.J.; Muratcioglu, S.; Jang, H.; Gursoy, A.; Keskin, O. Principles of K-Ras effector organization and the role of oncogenic K-Ras in cancer initiation through G1 cell cycle deregulation. Expert Rev. Proteomics, 2015, 12(6), 669-682.
[http://dx.doi.org/10.1586/14789450.2015.1100079] [PMID: 26496174]
[6]
Buscail, L.; Bournet, B.; Cordelier, P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol., 2020, 17(3), 153-168.
[http://dx.doi.org/10.1038/s41575-019-0245-4] [PMID: 32005945]
[7]
Goitre, L.; Trapani, E.; Trabalzini, L.; Retta, S.F. The Ras Superfamily of Small GTPases: The Unlocked Secrets.Ras Signaling: Methods and Protocols; Trabalzini, L; Retta, S.F., Ed.; Humana Press: Totowa, NJ, 2014, pp. 1-18.
[http://dx.doi.org/10.1007/978-1-62703-791-4_1]
[8]
Timar, J.; Kashofer, K. Molecular epidemiology and diagnostics of KRAS mutations in human cancer. Cancer Metastasis Rev., 2020, 39(4), 1029-1038.
[http://dx.doi.org/10.1007/s10555-020-09915-5] [PMID: 32725342]
[9]
Palmarocchi, M.C.; Fratti, M. Research progress on KRAS mutations in colorectal cancer.1. J. Cancer Metastasis Treat., 2021, 7.
[10]
Arrington, A.K.; Heinrich, E.L.; Lee, W.; Duldulao, M.; Patel, S.; Sanchez, J.; Garcia-Aguilar, J.; Kim, J. Prognostic and predictive roles of KRAS mutation in colorectal cancer. Int. J. Mol. Sci., 2012, 13(12), 12153-12168.
[http://dx.doi.org/10.3390/ijms131012153] [PMID: 23202889]
[11]
Gorfe, A.A.; Cho, K.J. Approaches to inhibiting oncogenic K-Ras. Small GTPases, 2021, 12(2), 96-105.
[http://dx.doi.org/10.1080/21541248.2019.1655883] [PMID: 31438765]
[12]
Sogabe, S.; Kamada, Y.; Miwa, M.; Niida, A.; Sameshima, T.; Kamaura, M.; Yonemori, K.; Sasaki, S.; Sakamoto, J.; Sakamoto, K. Crystal Structure of a Human K-Ras G12D Mutant in Complex with GDP and the Cyclic Inhibitory Peptide KRpep-2d. ACS Med. Chem. Lett., 2017, 8(7), 732-736.
[http://dx.doi.org/10.1021/acsmedchemlett.7b00128] [PMID: 28740607]
[13]
S. Hiraokaet al Laterally Spreading Type of Colorectal Adenoma Exhibits a Unique Methylation Phenotype and K-ras Mutations. Gastroenterology, 2006, 131(2), 379-389.
[http://dx.doi.org/10.1053/j.gastro.2006.04.027]
[14]
Liu, P.; Wang, Y.; Li, X. Targeting the untargetable KRAS in cancer therapy. Acta Pharm. Sin. B, 2019, 9(5), 871-879.
[http://dx.doi.org/10.1016/j.apsb.2019.03.002] [PMID: 31649840]
[15]
Osaka, N.; Hirota, Y.; Ito, D.; Ikeda, Y.; Kamata, R.; Fujii, Y.; Chirasani, V.R.; Campbell, S.L.; Takeuchi, K.; Senda, T.; Sasaki, A.T. Divergent Mechanisms Activating RAS and Small GTPases Through Post-translational Modification. Front. Mol. Biosci., 2021, 8, 707439.
[http://dx.doi.org/10.3389/fmolb.2021.707439] [PMID: 34307463]
[16]
Navarro-Lérida, I.; Sánchez-Álvarez, M.; del Pozo, M.Á. Post-Translational Modification and Subcellular Compartmentalization: Emerging Concepts on the Regulation and Physiopathological Relevance of RhoGTPases. Cells, 2021, 10(8), 1990.
[http://dx.doi.org/10.3390/cells10081990] [PMID: 34440759]
[17]
Leonard, D.M. Ras farnesyltransferase: A new therapeutic target. J. Med. Chem., 1997, 40(19), 2971-2990.
[http://dx.doi.org/10.1021/jm970226l] [PMID: 9301658]
[18]
Cho, K.N.; Lee, K.I. Chemistry and biology of ras farnesyltransferase. Arch. Pharm. Res., 2002, 25(6), 759-769.
[http://dx.doi.org/10.1007/BF02976989] [PMID: 12510823]
[19]
Wang, W.; Yuan, T.; Qian, M.; Yan, F.; Yang, L.; He, Q.; Yang, B.; Lu, J.; Zhu, H. Post-translational modification of KRAS: Potential targets for cancer therapy. Acta Pharmacol. Sin., 2021, 42(8), 1201-1211.
[http://dx.doi.org/10.1038/s41401-020-00542-y] [PMID: 33087838]
[20]
Ahearn, I.M.; Haigis, K.; Bar-Sagi, D.; Philips, M.R. Regulating the regulator: Post-translational modification of RAS. Nat. Rev. Mol. Cell Biol., 2012, 13(1), 39-51.
[http://dx.doi.org/10.1038/nrm3255] [PMID: 22189424]
[21]
Friday, B.B.; Adjei, A.A. K-ras as a target for cancer therapy. Biochim. Biophys. Acta Rev. Cancer, 2005, 1756(2), 127-144.
[http://dx.doi.org/10.1016/j.bbcan.2005.08.001] [PMID: 16139957]
[22]
Bergo, M.O.; Leung, G.K.; Ambroziak, P.; Otto, J.C.; Casey, P.J.; Young, S.G. Targeted inactivation of the isoprenylcysteine carboxyl methyltransferase gene causes mislocalization of K-Ras in mammalian cells. J. Biol. Chem., 2000, 275(23), 17605-17610.
[http://dx.doi.org/10.1074/jbc.C000079200] [PMID: 10747846]
[23]
Bergo, M.O.; Gavino, B.J.; Hong, C.; Beigneux, A.P.; McMahon, M.; Casey, P.J.; Young, S.G. Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J. Clin. Invest., 2004, 113(4), 539-550.
[http://dx.doi.org/10.1172/JCI200418829] [PMID: 14966563]
[24]
Yang, W.S.; Yeo, S.G.; Yang, S.; Kim, K.H.; Yoo, B.C.; Cho, J.Y. Isoprenyl carboxyl methyltransferase inhibitors: A brief review including recent patents. Amino Acids, 2017, 49(9), 1469-1485.
[http://dx.doi.org/10.1007/s00726-017-2454-x] [PMID: 28631011]
[25]
Ramanujulu, P.M.; Yang, T.; Yap, S.Q.; Wong, F.C.; Casey, P.J.; Wang, M.; Go, M.L. Functionalized indoleamines as potent, drug-like inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt). Eur. J. Med. Chem., 2013, 63, 378-386.
[http://dx.doi.org/10.1016/j.ejmech.2013.02.007] [PMID: 23514631]
[26]
Lau, H.Y.; Ramanujulu, P.M.; Guo, D.; Yang, T.; Wirawan, M.; Casey, P.J.; Go, M.L.; Wang, M. An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo. Cancer Biol. Ther., 2014, 15(9), 1280-1291.
[http://dx.doi.org/10.4161/cbt.29692] [PMID: 24971579]
[27]
Studio, B.D. BIOVIA, DassaultSystèmes, Discovery Studio Modeling Environment, v16.1.0; BIOVIA Discovery Studio: San Diego, CA, 2016.
[28]
Sterling, T.; Irwin, J.J. ZINC 15 – Ligand Discovery for Everyone. J. Chem. Inf. Model., 2015, 55(11), 2324-2337.
[http://dx.doi.org/10.1021/acs.jcim.5b00559] [PMID: 26479676]
[29]
Asinex 2016. Available From: http://www.asinex.com
[30]
Cheng, A.; Merz, K.M., Jr Prediction of aqueous solubility of a diverse set of compounds using quantitative structure-property relationships. J. Med. Chem., 2003, 46(17), 3572-3580.
[http://dx.doi.org/10.1021/jm020266b] [PMID: 12904062]
[31]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[32]
Hewitt, M.; Cronin, M.T.D.; Enoch, S.J.; Madden, J.C.; Roberts, D.W.; Dearden, J.C. In silico prediction of aqueous solubility: The solubility challenge. J. Chem. Inf. Model., 2009, 49(11), 2572-2587.
[http://dx.doi.org/10.1021/ci900286s] [PMID: 19877720]
[33]
Ali, J.; Camilleri, P.; Brown, M.B.; Hutt, A.J.; Kirton, S.B. In silico prediction of aqueous solubility using simple QSPR models: The importance of phenol and phenol-like moieties. J. Chem. Inf. Model., 2012, 52(11), 2950-2957.
[http://dx.doi.org/10.1021/ci300447c] [PMID: 23121381]
[34]
Delaney, J.S. ESOL: Estimating aqueous solubility directly from molecular structure. J. Chem. Inf. Comput. Sci., 2004, 44(3), 1000-1005.
[http://dx.doi.org/10.1021/ci034243x] [PMID: 15154768]
[35]
Pires, D.E.V.; Blundell, T.L.; Ascher, D.B. pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. J. Med. Chem., 2015, 58(9), 4066-4072.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00104] [PMID: 25860834]
[36]
Khan, A.Q.; Kuttikrishnan, S.; Siveen, K.S.; Prabhu, K.S.; Shanmugakonar, M. Al-Naemi, H.A.; Haris, M.; Dermime, S.; Uddin, S. RAS-mediated oncogenic signaling pathways in human malignancies. Semin. Cancer Biol., 2019, 54, 1-13.
[http://dx.doi.org/10.1016/j.semcancer.2018.03.001] [PMID: 29524560]
[37]
Greenhough, A.; Patsos, H.A.; Williams, A.C.; Paraskeva, C. The cannabinoid δ 9 ‐tetrahydrocannabinol inhibits RAS‐MAPK and PI3K‐AKT survival signalling and induces BAD‐mediated apoptosis in colorectal cancer cells. Int. J. Cancer, 2007, 121(10), 2172-2180.
[http://dx.doi.org/10.1002/ijc.22917] [PMID: 17583570]
[38]
Pantsar, T. The current understanding of KRAS protein structure and dynamics. Comput. Struct. Biotechnol. J., 2020, 18, 189-198.
[http://dx.doi.org/10.1016/j.csbj.2019.12.004] [PMID: 31988705]
[39]
Lau, H.Y.; Tang, J.; Casey, P.J.; Wang, M. Isoprenylcysteine carboxylmethyltransferase is critical for malignant transformation and tumor maintenance by all RAS isoforms. Oncogene, 2017, 36(27), 3934-3942.
[http://dx.doi.org/10.1038/onc.2016.508] [PMID: 28192404]
[40]
Wang, M.; Tan, W.; Zhou, J.; Leow, J.; Go, M.; Lee, H.S.; Casey, P.J. A small molecule inhibitor of isoprenylcysteine carboxymethyltransferase induces autophagic cell death in PC3 prostate cancer cells. J. Biol. Chem., 2008, 283(27), 18678-18684.
[http://dx.doi.org/10.1074/jbc.M801855200] [PMID: 18434300]

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