PDBsum entry 4wrs

Transferase/transferase inhibitor

PDB id: 4wrs

Contents

Protein chain

273 a.a.

Ligands

GOL ×2

3U1

Waters ×142

PDB id:

4wrs

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of human pim-1 kinase in complex with an azaspiro pyrazinyl-indazole inhibitor.

Structure:

Serine/threonine-protein kinase pim-1. Chain: a. Fragment: unp residues 124-396. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pim1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.20Å R-factor: 0.180 R-free: 0.208

Authors:

C.Mohr

Key ref:

H.L.Wang et al. (2015). The discovery of novel 3-(pyrazin-2-yl)-1H-indazoles as potent pan-Pim kinase inhibitors. Bioorg Med Chem Lett, 25, 834-840. PubMed id: 25597005 DOI: 10.1016/j.bmcl.2014.12.068

Date:

25-Oct-14 Release date: 04-Feb-15

Protein chain

P11309  (PIM1_HUMAN) -  Serine/threonine-protein kinase pim-1 from Homo sapiens

Seq: 313 a.a.

Struc: 273 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.bmcl.2014.12.068

Bioorg Med Chem Lett 25:834-840 (2015)

PubMed id: 25597005

The discovery of novel 3-(pyrazin-2-yl)-1H-indazoles as potent pan-Pim kinase inhibitors.

H.L.Wang, V.J.Cee, F.Chavez, B.A.Lanman, A.B.Reed, B.Wu, N.Guerrero, J.R.Lipford, C.Sastri, J.Winston, K.L.Andrews, X.Huang, M.R.Lee, C.Mohr, Y.Xu, Y.Zhou, A.S.Tasker.

ABSTRACT

The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to tumorigenesis. As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Herein, we describe our efforts toward the development of a potent, pan-Pim inhibitor. The synthesis and hit-to-lead SAR development from a 3-(pyrazin-2-yl)-1H-indazole derived hit 2 to the identification of a series of potent, pan-Pim inhibitors such as 13o are described.