Format

Send to

Choose Destination
Eur J Med Chem. 2016 May 4;113:273-92. doi: 10.1016/j.ejmech.2016.02.006. Epub 2016 Feb 4.

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

Author information

1
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
2
School of Chemistry, University of Cardiff, CF10 3AT, UK.
3
Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA.
4
PharmD Program, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
5
Bryn Mawr School, 109 W. Melrose Ave., Baltimore, MD 21210, USA.
6
Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA.
7
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA; University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA.
8
Department of Biochemistry and Molecular Biology, Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 22 S. Greene St., Baltimore, MD 21201, USA; University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA.
9
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA; University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA. Electronic address: sfletcher@rx.umaryland.edu.

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.

KEYWORDS:

Apoptosis; Bcl-x(L); Cancer; Mcl-1; Protein–protein interaction

PMID:
26985630
PMCID:
PMC4811700
DOI:
10.1016/j.ejmech.2016.02.006
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center