General Ser/Thr Kinases Pharmacophore Approach for Selective Kinase Inhibitors Search as Exemplified by Design of Potent and Selective Aurora A Inhibitors

Natalya I Vasilevich; Elena A Aksenova; Denis N Kazyulkin; Ilya I Afanasyev

doi:10.1111/cbdd.12733

General Ser/Thr Kinases Pharmacophore Approach for Selective Kinase Inhibitors Search as Exemplified by Design of Potent and Selective Aurora A Inhibitors

Chem Biol Drug Des. 2016 Jul;88(1):54-65. doi: 10.1111/cbdd.12733. Epub 2016 Feb 20.

Authors

Natalya I Vasilevich¹, Elena A Aksenova¹, Denis N Kazyulkin¹, Ilya I Afanasyev¹

Affiliation

¹ Novie Nauchnie Tekhnologii Ltd. (ASINEX Company Group), 20 Geroev Panfilovtsev Str., Moscow, 125480, Russia.

PMID: 26825399
DOI: 10.1111/cbdd.12733

Abstract

A general pharmachophore model for various types of Ser/Thr kinases was developed. Search for the molecules fitting to this pharmacophore among ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against several Ser/Thr kinases such as Aurora A, Aurora B and Haspin. The possibility of performing the fine-tuning of the general Ser/Thr pharmacophore to desired types of kinase to get active and selective inhibitors was exemplified by Aurora A kinase. As a result, several hits in 3-5 nm range of activity against Aurora A kinase with rather good selectivity and ADME properties were obtained.

Keywords: kinase; molecular modeling; pharmacophore modeling; phosphatase; structure-based drug design.

Publication types

Letter
Research Support, Non-U.S. Gov't

MeSH terms

Aurora Kinase A* / antagonists & inhibitors
Aurora Kinase A* / chemistry
Humans
Models, Molecular*
Protein Kinase Inhibitors / chemistry*

Substances

Protein Kinase Inhibitors
AURKA protein, human
Aurora Kinase A