Design and Synthesis of Potent and Selective PIM Kinase Inhibitors by Targeting Unique Structure of ATP-Binding Pocket

ACS Medicinal Chemistry Letters
Hirofumi NakanoTetsuo Nagano

Abstract

In the development of kinase inhibitors, one of the major concerns is selectivity. An effective strategy to achieve high selectivity is to utilize structural differences among kinases to inform inhibitor design. Here, we set out to improve the PIM (proviral integration site for Moloney murine leukemia virus) kinase-inhibitory selectivity of our previously reported 7-azaindole derivative 2, which has promising ADMET properties, by targeting a unique bulge in the ATP-binding pocket. 6-Substituted 7-azaindoles, especially the 6-chlorinated derivatives, proved to be potent and selective PIM kinase inhibitors and appear to be promising lead compounds for future drug discovery.

References

Nov 5, 2004·The Journal of Biological Chemistry·Kevin C QianBennett Farmer
Jan 20, 2005·The Journal of Biological Chemistry·Marc D JacobsKumkum Saxena
Nov 1, 2007·Nature Reviews. Drug Discovery·Paul D Leeson, Brian Springthorpe
Jan 27, 2010·Expert Opinion on Therapeutic Patents·Tina Morwick
Oct 6, 2010·Future Oncology·Nancy S MagnusonRaymond Reeves
Dec 15, 2010·Nature Reviews. Cancer·Martijn C NawijnAnton Berns
Apr 27, 2011·Cancer Science·Naofumi MukaidaYing-Yi Li
May 10, 2011·Annual Review of Biochemistry·Arvin C Dar, Kevan M Shokat
Aug 8, 2012·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Lorien J ParkerAkiko Tanaka
Aug 29, 2012·Journal of Medicinal Chemistry·Denis DryginDavid M Ryckman
Oct 18, 2013·Expert Opinion on Therapeutic Patents·Gubbi M AruneshVellarkad N Viswanadhan
Jan 30, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Pablo D GarciaMatthew T Burger
Dec 9, 2014·ACS Chemical Biology·Michael Tong, Markus A Seeliger
May 16, 2015·Trends in Pharmacological Sciences·Peng WuMads H Clausen
Sep 12, 2015·Bioorganic & Medicinal Chemistry·Li XingElizabeth A Lunney

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