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

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TitleStructure-based design of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoates as selective inhibitors of the Mcl-1 oncoprotein.
Publication TypeJournal Article
Year of Publication2016
AuthorsLanning, 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, Wilder, PT, Fletcher, S
JournalEur J Med Chem
Volume113
Pagination273-92
Date Published2016 May 04
ISSN1768-3254
KeywordsCarboxylic Acids, Cell Line, Tumor, Cell Proliferation, Cell Survival, Dose-Response Relationship, Drug, Drug Design, Humans, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Molecular Structure, Myeloid Cell Leukemia Sequence 1 Protein, Naphthalenes, Structure-Activity Relationship
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.

DOI10.1016/j.ejmech.2016.02.006
Alternate JournalEur J Med Chem
PubMed ID26985630
PubMed Central IDPMC4811700
Grant ListR43 GM109635 / GM / NIGMS NIH HHS / United States
T32 GM066706 / GM / NIGMS NIH HHS / United States
R43GM109635 / GM / NIGMS NIH HHS / United States
T32GM066706 / GM / NIGMS NIH HHS / United States