PDBsum entry 3umw

Transferase/inhibitor

PDB id: 3umw

Contents

Protein chain

264 a.a.

Ligands

GOL

SO4

596

Waters ×237

PDB id:

3umw

Name:

Transferase/inhibitor

Title:

Crystal structure of pim1 kinase in complex with inhibitor (z)-2-[(1h- indazol-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran- 3(2h)-one

Structure:

Proto-oncogene serine/threonine-protein kinase pim-1. Chain: a. Fragment: kinase domain (unp residues 120-404). Engineered: yes

Source:

Homo sapiens. Organism_taxid: 9606. Gene: pim1. Expressed in: cell-free protein synthesis.

Resolution:

2.08Å R-factor: 0.175 R-free: 0.200

Authors:

L.J.Parker,N.Handa,S.Yokoyama

Key ref:

H.Nakano et al. (2012). Rational evolution of a novel type of potent and selective proviral integration site in Moloney murine leukemia virus kinase 1 (PIM1) inhibitor from a screening-hit compound. J Med Chem, 55, 5151-5164. PubMed id: 22540945

Date:

14-Nov-11 Release date: 03-Oct-12

Protein chain

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

Seq: 313 a.a.

Struc: 264 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

J Med Chem 55:5151-5164 (2012)

PubMed id: 22540945

Rational evolution of a novel type of potent and selective proviral integration site in Moloney murine leukemia virus kinase 1 (PIM1) inhibitor from a screening-hit compound.

H.Nakano, N.Saito, L.Parker, Y.Tada, M.Abe, K.Tsuganezawa, S.Yokoyama, A.Tanaka, H.Kojima, T.Okabe, T.Nagano.

ABSTRACT

Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.