Structural Analysis of PIM1 Kinase Complexes with ATP-competitive Inhibitors

Overview

Journal Sci Rep

Specialty Science

Date 2017 Oct 19

PMID 29042609

Citations 11

Authors

Jozefina Bogusz

Karol Zrubek

Krzysztof P Rembacz

Przemyslaw Grudnik

Przemyslaw Golik

Malgorzata Romanowska

Benedykt Wladyka

Grzegorz Dubin

Affiliations

Soon will be listed here.

Abstract

PIM1 is an oncogenic kinase overexpressed in a number of cancers where it correlates with poor prognosis. Several studies demonstrated that inhibition of PIM1 activity is an attractive strategy in fighting overexpressing cancers, while distinct structural features of ATP binding pocket make PIM1 an inviting target for the design of selective inhibitors. To facilitate development of specific PIM1 inhibitors, in this study we report three crystal structures of ATP-competitive inhibitors at the ATP binding pocket of PIM1. Two of the reported structures (CX-4945 and Ro-3306) explain the off-target effect on PIM1 of respectively casein kinase 2 and cyclin-dependent kinase 1 dedicated inhibitors. In turn, the structure with CX-6258 demonstrates a binding mode of a potent, selective inhibitor of PIM1, PIM2, PIM3 and Flt-3 kinases. The consequences of our findings for future inhibitor development are discussed.

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