5EOL

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

Summary for 5EOL

• Entry DOI: 10.2210/pdb5eol/pdb
• Descriptor: Serine/threonine-protein kinase pim-1, macrocyclic quinoxaline-pyrrolodihydropiperidinone, 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: 33608.03

Authors

Mohr, C. (deposition date: 2015-11-10, release date: 2016-05-04, Last modification date: 2024-03-06)

Primary citation

Cee, V.J.,Chavez, F.,Herberich, B.,Lanman, B.A.,Pettus, L.H.,Reed, A.B.,Wu, B.,Wurz, R.P.,Andrews, K.L.,Chen, J.,Hickman, D.,Laszlo, J.,Lee, M.R.,Guerrero, N.,Mattson, B.K.,Nguyen, Y.,Mohr, C.,Rex, K.,Sastri, C.E.,Wang, P.,Wu, Q.,Wu, T.,Xu, Y.,Zhou, Y.,Winston, J.T.,Lipford, J.R.,Tasker, A.S.,Wang, H.L.
Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors.
Acs Med.Chem.Lett., 7:408-412, 2016

PubMed 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.

PubMed: 27096050
DOI: 10.1021/acsmedchemlett.5b00403

Experimental method

X-RAY DIFFRACTION (2.2 Å)