6no9
PIM1 in complex with Cpd16 (5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide)PIM1 in complex with Cpd16 (5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide)
Structural highlights
FunctionPIM1_HUMAN Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedPim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate. Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma.,Wang X, Blackaby W, Allen V, Chan GKY, Chang JH, Chiang PC, Diene C, Drummond J, Do S, Fan E, Harstad EB, Hodges A, Hu H, Jia W, Kofie W, Kolesnikov A, Lyssikatos JP, Ly J, Matteucci M, Moffat JG, Munugalavadla V, Murray J, Nash D, Noland CL, Del Rosario G, Ross L, Rouse C, Sharpe A, Slaga D, Sun M, Tsui V, Wallweber H, Yu SF, Ebens AJ J Med Chem. 2019 Feb 20. doi: 10.1021/acs.jmedchem.8b01857. PMID:30715878[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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