Issue 9, 2012
From the journal:

MedChemComm

Identification of a novel nanomolar inhibitor of hIcmt via a carboxylate replacement approach†

Jaimeen D. Majmudar,ac   Amanda Morrison-Logue,bc   Jiao Song,ac   Christine A. Hrycyna*bc  and  Richard A. Gibbs*ac  

* Corresponding authors

a Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
E-mail: rgibbs@purdue.edu

b Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
E-mail: hrycyna@purdue.edu

c The Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA

Abstract

A substrate-based approach to human isoprenylcysteine carboxyl methyltransferase (hIcmt) inhibitors via systematic modulation of both the amide and the prenyl regions of N-acetyl-S-farnesyl-L-cysteine (AFC) led to potent inhibitors of this promising anti-cancer target. However, to date, molecules containing changes to the important carboxylate pharmacophore have not been extensively explored as Icmt inhibitors. We synthesized a set of 39 analogs in which the carboxylate region was chemically redefined using a farnesyl thiopropionic acid (FTPA) backbone. Herein, we demonstrated that modifications of carboxylate motif can lead to potent, sub-micromolar inhibitor of the enzyme. Our most potent inhibitor, analog 12, demonstrated an in vitro IC50 value of 860 nM and cellular effects consistent with hIcmt inhibition.

Graphical abstract: Identification of a novel nanomolar inhibitor of hIcmt via a carboxylate replacement approach

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Article information

DOI
https://doi.org/10.1039/C2MD20108A
Article type
Concise Article
Submitted
30 Apr 2012
Accepted
26 Jun 2012
First published
03 Aug 2012

Med. Chem. Commun., 2012,3, 1125-1137

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Identification of a novel nanomolar inhibitor of hIcmt via a carboxylate replacement approach

J. D. Majmudar, A. Morrison-Logue, J. Song, C. A. Hrycyna and R. A. Gibbs, Med. Chem. Commun., 2012, 3, 1125 DOI: 10.1039/C2MD20108A

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