Abstract:
:We recently described the discovery of a dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1). Here we report a structure-guided design in combination with structure-activity relationship studies to exploit the difference in the p2 binding pocket of Bcl-2 and Mcl-1, from which a novel dual inhibitor 3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (6h) was obtained, which showed significant enhanced IC(50) value against Mcl-1 (5 nM), greater Mcl-1/Bak disruption potential, and accordingly a 10-fold increased cytotoxicity over 3.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Zhang Z,Wu G,Xie F,Song T,Chang Xdoi
10.1021/jm101181usubject
Has Abstractpub_date
2011-02-24 00:00:00pages
1101-5issue
4eissn
0022-2623issn
1520-4804journal_volume
54pub_type
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