Sahand Golestanian1, Amirhossein Sharifi1, Grzegorz M Popowicz2, Homa Azizian3, Alireza Foroumadi1, Aleksandra Szwagierczak2, Tad A Holak4, Massoud Amanlou5. 1. Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design and Development Research Center, Tehran University of Medical Sciences, 16 Azar Ave., Tehran, Iran. 2. Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. 3. Department of Medicinal Chemistry, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran. 4. Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. Electronic address: holak@biochem.mpg.de. 5. Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design and Development Research Center, Tehran University of Medical Sciences, 16 Azar Ave., Tehran, Iran. Electronic address: amanlou@tums.ac.ir.
Abstract
AIMS: The p53 protein, also called guardian of the genome, has a key role in cell cycle regulation. It is activated under stressful circumstances, such as DNA damage which results in permanent arrest or cell death. The protein is disabled in several types of human cancer due to over-expression of the two regulators, Mdm2 and Mdmx. As a result, inhibiting Mdm subtypes could reactivate p53 and bring about a promising therapeutic strategy in cancers. MAIN METHODS: Here a structure-based pharmacophore search and docking simulation are presented in order to filter our in-house library which contains 1035 compounds to find novel scaffolds that inhibit Mdm2 and Mdmx concomitantly. Afterwards, fluorescence polarization binding assay was used to obtain inhibition constant of final compounds. KEY FINDINGS: Thirty two ligands were introduced to bioassay as a result of in-silico methods. Twelve of them inhibit both proteins with almost balanced Ki value ranging from 18 to 162μM for Mdm2 and 18 to 233μM for Mdmx. It was observed that all compounds fill Phe19 and Trp23 pockets of Mdm2/x binding sites and form a hydrogen bond with Trp23 pocket's neighbor amino acids in a manner similar to p53 protein. Additionally, it was concluded that Trp23 pocket of Mdmx has a bigger hydrophobic volume comparing with the one of Mdm2. SIGNIFICANCE: Three structure-activity relationship patterns are supposed which one of them presents usefulness features and can be used in future studies. This study presents first qualitative SAR for dual inhibitors against Mdm2/x.
AIMS: The p53 protein, also called guardian of the genome, has a key role in cell cycle regulation. It is activated under stressful circumstances, such as DNA damage which results in permanent arrest or cell death. The protein is disabled in several types of humancancer due to over-expression of the two regulators, Mdm2 and Mdmx. As a result, inhibiting Mdm subtypes could reactivate p53 and bring about a promising therapeutic strategy in cancers. MAIN METHODS: Here a structure-based pharmacophore search and docking simulation are presented in order to filter our in-house library which contains 1035 compounds to find novel scaffolds that inhibit Mdm2 and Mdmx concomitantly. Afterwards, fluorescence polarization binding assay was used to obtain inhibition constant of final compounds. KEY FINDINGS: Thirty two ligands were introduced to bioassay as a result of in-silico methods. Twelve of them inhibit both proteins with almost balanced Ki value ranging from 18 to 162μM for Mdm2 and 18 to 233μM for Mdmx. It was observed that all compounds fill Phe19 and Trp23 pockets of Mdm2/x binding sites and form a hydrogen bond with Trp23 pocket's neighbor amino acids in a manner similar to p53 protein. Additionally, it was concluded that Trp23 pocket of Mdmx has a bigger hydrophobic volume comparing with the one of Mdm2. SIGNIFICANCE: Three structure-activity relationship patterns are supposed which one of them presents usefulness features and can be used in future studies. This study presents first qualitative SAR for dual inhibitors against Mdm2/x.
Authors: Sharon Min Qi Chee; Jantana Wongsantichon; Jiawei Siau; Dawn Thean; Fernando Ferrer; Robert C Robinson; David P Lane; Christopher J Brown; Farid J Ghadessy Journal: PLoS One Date: 2017-12-11 Impact factor: 3.240
Authors: Stephen L Abrams; Peter P Ruvolo; Vivian R Ruvolo; Giovanni Ligresti; Alberto M Martelli; Lucio Cocco; Stefano Ratti; Agostino Tafuri; Linda S Steelman; Saverio Candido; Massimo Libra; James A McCubrey Journal: Oncotarget Date: 2017-08-24