PDBsum entry 5eol

Transferase/transferase inhibitor

PDB id: 5eol

Contents

Protein chain

273 a.a.

Ligands

5QO

GOL ×2

Waters ×103

PDB id:

5eol

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of human pim-1 kinase in complex with a macrocyclic quinoxaline-pyrrolodihydropiperidinone inhibitor

Structure:

Serine/threonine-protein kinase pim-1. Chain: a. Engineered: yes

Source:

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

Resolution:

2.20Å R-factor: 0.196 R-free: 0.223

Authors:

C.Mohr

Key ref:

V.J.Cee et al. (2016). Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors. Acs Med Chem Lett, 7, 408-412. PubMed id: 27096050 DOI: 10.1021/acsmedchemlett.5b00403

Date:

10-Nov-15 Release date: 04-May-16

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: 10.1021/acsmedchemlett.5b00403

Acs Med Chem Lett 7:408-412 (2016)

PubMed id: 27096050

Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors.

V.J.Cee, F.Chavez, B.Herberich, B.A.Lanman, L.H.Pettus, A.B.Reed, B.Wu, R.P.Wurz, K.L.Andrews, J.Chen, D.Hickman, J.Laszlo, M.R.Lee, N.Guerrero, B.K.Mattson, Y.Nguyen, C.Mohr, K.Rex, C.E.Sastri, P.Wang, Q.Wu, T.Wu, Y.Xu, Y.Zhou, J.T.Winston, J.R.Lipford, A.S.Tasker, H.L.Wang.

ABSTRACT

The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization and developed a series of 13-membered macrocycles. The structure-activity relationships of the macrocyclic linker were systematically explored, leading to the identification of 9c as a potent, subnanomolar inhibitor of Pim-1 and -2. This molecule also potently inhibited Pim kinase activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2, both in vitro (pBAD IC50 = 25 nM) and in vivo (pBAD EC50 = 30 nM, unbound), and a 100 mg/kg daily dose was found to completely arrest the growth of KMS-12-BM xenografts in mice.