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Bioorg Med Chem Lett. 2015 Feb 1;25(3):474-80. doi: 10.1016/j.bmcl.2014.12.041. Epub 2014 Dec 19.

Structure-based design of low-nanomolar PIM kinase inhibitors.

Author information

1
Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA. Electronic address: al_ishchenko@yahoo.com.
2
Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
3
Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA; EMD Serono Research and Development Institute, 45A Middlesex Turnpike, Billerica, MA 01821, USA.
4
Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA; Department of Chemistry, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, Republic of Korea.

Abstract

PIM kinases are implicated in variety of cancers by promoting cell survival and proliferation and are targets of interest for therapeutic intervention. We have identified a low-nanomolar pan-PIM inhibitor (PIM1/2/3 potency 5:14:2nM) using structure based modeling. The crystal structure of this compound with PIM1 confirmed the predicted binding mode and protein-ligand interactions except those in the acidic ribose pocket. We show the SAR suggesting the importance of having a hydrogen bond donor in this pocket for inhibiting PIM2; however, this interaction is not important for inhibiting PIM1 or PIM3. In addition, we report the discovery of a new class of PIM inhibitors by using computational de novo design tool implemented in MOE software (Chemical Computing Group). These inhibitors have a different interaction profile.

KEYWORDS:

De novo design; Kinase inhibitors; PIM; PIM inhibitors; Rational design

PMID:
25575657
DOI:
10.1016/j.bmcl.2014.12.041
[Indexed for MEDLINE]

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