Icmt inhibitor development: Merging bioisosterism and computational tools for the identification of potent nanomolar Icmt inhibitors

Jaimeen Devraj Majmudar, Purdue University

Abstract

Mutated K-ras remains constitutively in the active GTP-bound state, signaling continuously, resulting in tumorogenesis. An approach to inhibit Ras signaling involves inhibition of the enzymes that post-translationally modify Ras. Icmt is an enzyme that methyl esterifies Ras proteins, resulting in increased hydrophobicity and membrane association. Our initial attempts involved isosteric amide bond replacement of N-acetyl- S-farnesyl cysteine (AFC, minimal peptidic Icmt substrate) with various bioisosteres to achieve Icmt inhibition. This study led to the discovery of low micromolar Icmt inhibitors and alternative Icmt substrates. Through a focused study on one of our initial leads, phenoxy-phenyl farnesyl cysteine (POP-FC), we learned that the most important feature required for Icmt inhibition was the prenyl group. We then moved further to evaluate the importance of the carboxylate motif by replacing it with various functional groups. This study led to a submicromolar inhibitor of Icmt. The final project in this thesis concerns the development of a QSAR model based on the newly discovered STAB class of Icmt inhibitors. Upon identification of low sub-micromolar leads, we initiated a QSAR development project in conjunction with the laboratory of Dr. Markus Lill. We successfully generated a predictive QSAR model (r 2=0.82, p2= 0.72) and have validated it experimentally. This investigation has provided us with insight into the inhibition requirements for hIcmt. The lead molecule generated through this study is an extremely potent hIcmt inhibitor and exhibits promising activity in pancreatic tumor cells.

Degree

Ph.D.

Advisors

Gibbs, Purdue University.

Subject Area

Chemistry|Biochemistry|Oncology

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