5IPJ

Crystal structure of human Pim-1 kinase in complex with a quinazolinone-pyrrolopyrrolone inhibitor.

Summary for 5IPJ

• Entry DOI: 10.2210/pdb5ipj/pdb
• Descriptor: Serine/threonine-protein kinase pim-1, 2-(tert-butylamino)-3-methyl-8-[(6R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl]quinazolin-4(3H)-one, GLYCEROL, ... (4 entities in total)
• Functional Keywords: transferase, serine/threonine protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309
• Total number of polymer chains: 1
• Total formula weight: 33706.13

Authors

Mohr, C. (deposition date: 2016-03-09, release date: 2016-06-22, Last modification date: 2024-03-06)

Primary citation

Pettus, L.H.,Andrews, K.L.,Booker, S.K.,Chen, J.,Cee, V.J.,Chavez, F.,Chen, Y.,Eastwood, H.,Guerrero, N.,Herberich, B.,Hickman, D.,Lanman, B.A.,Laszlo, J.,Lee, M.R.,Lipford, J.R.,Mattson, B.,Mohr, C.,Nguyen, Y.,Norman, M.H.,Powers, D.,Reed, A.B.,Rex, K.,Sastri, C.,Tamayo, N.,Wang, P.,Winston, J.T.,Wu, B.,Wu, T.,Wurz, R.P.,Xu, Y.,Zhou, Y.,Tasker, A.S.,Wang, H.L.
Discovery and Optimization of Quinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable Pan-Pim Kinase Inhibitors.
J.Med.Chem., 59:6407-6430, 2016

PubMed Abstract: The high expression of proviral insertion site of Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role in promoting cell survival and proliferation while suppressing apoptosis. The three isoforms of Pim protein appear largely redundant in their oncogenic functions. Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell active pan-Pim inhibitors have proven difficult to develop because Pim-2 has a low Km for ATP and therefore requires a very potent inhibitor to effectively block the kinase activity at cellular ATP concentrations. Herein, we report a series of quinazolinone-pyrrolopyrrolones as potent and selective pan-Pim inhibitors. In particular, compound 17 is orally efficacious in a mouse xenograft model (KMS-12 BM) of multiple myeloma, with 93% tumor growth inhibition at 50 mg/kg QD upon oral dosing.

PubMed: 27285051
DOI: 10.1021/acs.jmedchem.6b00610

Experimental method

X-RAY DIFFRACTION (2.1 Å)