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Indexed by:期刊论文

Date of Publication:2013-02-01

Journal:EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Included Journals:SCIE、PubMed、Scopus

Volume:60

Page Number:410-420

ISSN No.:0223-5234

Key Words:Fragment-based; Apoptosis; Mcl-1; LE; FQ

Abstract:We have previously reported a nanomolar inhibitor of antiapoptotic Mcl-1 protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1). S1 plays its function by binding to the BH3 groove of Mcl-1. Basing on this spacial structural characteristic, we developed a novel class of Mcl-1 inhibitor using fragment-based drug discovery approach. By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment. In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments. A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds Mcl-1 with an IC50 value of 54 nM was obtained. Compound 12c demonstrated a better aqueous solubility than S1. (C) 2012 Elsevier Masson SAS. All rights reserved.