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Structure-based design of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoates as selective inhibitors of the Mcl-1 oncoprotein.

Abstract：

:Structure-based drug design was utilized to develop novel, 1-hydroxy-2-naphthoate-based small-molecule inhibitors of Mcl-1. Ligand design was driven by exploiting a salt bridge with R263 and interactions with the p2 pocket of the protein. Significantly, target molecules were accessed in just two synthetic steps, suggesting further optimization will require minimal synthetic effort. Molecular modeling using the Site-Identification by Ligand Competitive Saturation (SILCS) approach was used to qualitatively direct ligand design as well as develop quantitative models for inhibitor binding affinity to Mcl-1 and the Bcl-2 relative Bcl-xL as well as for the specificity of binding to the two proteins. Results indicated hydrophobic interactions in the p2 pocket dominated affinity of the most favourable binding ligand (3bl: Ki = 31 nM). Compounds were up to 19-fold selective for Mcl-1 over Bcl-xL. Selectivity of the inhibitors was driven by interactions with the deeper p2 pocket in Mcl-1 versus Bcl-xL. The SILCS-based SAR of the present compounds represents the foundation for the development of Mcl-1 specific inhibitors with the potential to treat a wide range of solid tumours and hematological cancers, including acute myeloid leukemia.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Lanning ME,Yu W,Yap JL,Chauhan J,Chen L,Whiting E,Pidugu LS,Atkinson T,Bailey H,Li W,Roth BM,Hynicka L,Chesko K,Toth EA,Shapiro P,MacKerell AD Jr,Wilder PT,Fletcher S

doi

10.1016/j.ejmech.2016.02.006

subject

Has Abstract

pub_date

2016-05-04 00:00:00

pages

273-92

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(16)30075-7

journal_volume

113

pub_type

杂志文章

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