Last update 01 Nov 2024

ICMT

Last update 01 Nov 2024

Basic Info

Synonyms

HSTE14, ICMT, isoprenylcysteine carboxyl methyltransferase

+ [6]

Introduction

Catalyzes the post-translational methylation of isoprenylated C-terminal cysteine residues.

Drugs associated with ICMT

UCM-13207

Target

ICMT

Mechanism

ICMT inhibitors

Active Org.

Universidad Complutense de Madrid

Originator Org.

Universidad Complutense de Madrid

Active Indication

Hutchinson-Gilford progeria syndrome

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ICMT

100 Translational Medicine associated with ICMT

0 Patents (Medical) associated with ICMT

211

Literatures (Medical) associated with ICMT

01 Dec 2024·Current Computer-Aided Drug Design

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

Article

Author: Filali, Houda ; Mouhcine, Mohammed ; Segmani, Ibtihal ; Rahmoune, Imane ; Kadil, Youness

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.

08 Oct 2024·Proceedings of the National Academy of Sciences

Membrane association and polar localization of the Legionella pneumophila T4SS DotO ATPase mediated by two nonredundant receptors

Article

Author: Milek, Sonja ; Hasanovic, Ahmet ; Holgerson, Agnieszka ; Ghosal, Debnath ; Jensen, Grant J. ; Vogel, Joseph P. ; Maggi, Stefano ; Singh, Manpreet ; Vijayrajratnam, Sukhithasri ; Kannaiah, Shanmugapriya ; Ashen, Kaleigh ; Ferrell, Micah

The Legionella pneumophila Dot/Icm type IVB secretion system (T4BSS) is a large, multisubunit complex that exports a vast array of substrates into eukaryotic host cells. DotO, a distant homolog of the T4ASS ATPase VirB4, associates with the bacterial inner membrane despite lacking hydrophobic transmembrane domains. Employing a genetic approach, we found DotO’s membrane association is mediated by three inner-membrane Dot/Icm components, IcmT, and a combined DotJ–DotI complex (referred to as DotJI). Although deletion of icmT or dotJI individually does not affect DotO’s membrane association, the simultaneous inactivation of all three genes results in increased amounts of soluble DotO. Nevertheless, deleting each receptor separately profoundly affects positioning of DotO, disrupting its link with the Dot/Icm complex at the bacterial poles, rendering the receptors nonredundant. Furthermore, a collection of dotO point mutants that we isolated established that DotO’s N-terminal domain interacts with the membrane receptors and is involved in dimerization, whereas DotO’s C-terminal ATPase domain primarily contributes to the protein’s formation of oligomers. Modeling data revealed the complex interaction between DotO and its receptors is responsible for formation of DotO’s unique “hexamer of dimers” configuration, which is a defining characteristic of VirB4 family members.

01 Aug 2024·Cancer Genetics

Novel gene fusions in human oropharyngeal carcinoma

Article

Author: Matsushita, Hirokazu ; Masago, Katsuhiro ; Horio, Yoshitsugu ; Fujita, Shiro ; Ishihara, Hiromasa ; Hanai, Nobuhiro ; Fujita, Yasuko ; Kuroda, Hiroaki ; Sasaki, Eiichi ; Endo, Motoyoshi

Few reports have analyzed the fusion genes involved in carcinogenesis in the oropharynx, where the incidence of human papillomavirus-associated tumors is relatively low. The aim of this study was to identify novel driver fusion genes in patients with oropharyngeal cancer. The study enrolled fifty-seven patients who were diagnosed with oropharyngeal carcinoma. RNA sequencing data from fresh-frozen specimens were used to identify candidate fusion genes via the JAFFA, arriba, and STAR-Fusion pipelines. Candidate fusion genes were confirmed by direct sequencing. The expression level of a candidate fusion gene was compared to that of tumors without fusion genes. Finally, filtering was performed for driver genes using the annoFuse pipeline. In addition, the VIRTUS pipeline was used to analyze the presence of human papillomavirus in the tumors. We identified 5 (8.8 %) novel potential driver in-frame fusion genes, MKNK2::MOB3A, ICMT::RPS6KA3, ATP1B3::GRK7, CSNK2A1::KIF16B, and FGFR3::MAEA, and 1 (1.8 %) known in-frame fusion gene, FGFR3::TACC3, in 57 patients with pharyngeal carcinoma. Our results suggest that sporadic fusion genes may contribute to tumorigenesis in oropharyngeal carcinomas.

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