6mt0 | pdb_00006mt0
Crystal structure of human Pim-1 kinase in complex with a quinazolinone-pyrrolodihydropyrrolone inhibitor
Structural highlights
Function[PIM1_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 are a family of constitutively active serine/threonine kinases which are partially redundant and regulate multiple path-ways important for cell growth and survival. In human disease, high expression of the three Pim isoforms has been implicated in the progression of hematopoietic and solid tumor cancers, which suggests that Pim kinase inhibitors could provide patients with therapeutic benefit. Herein, we describe the structure-guided optimization of a series of quinazolinone-pyrrolodihydropyrrolone analogs leading to the identification of potent pan-Pim inhibitor 28 with improved potency, solubility and drug-like properties. Compound 28 demonstrated on-target Pim activity in an in vivo pharmacodynamic assay with significant inhibition of BAD phos-phorylation in KMS-12-BM multiple myeloma tumors for 16 hours post dose. In a 2-week mouse xenograft model, daily dosing of compound 28 resulted in 33% tumor regression at 100 mg/kg. Discovery of (R)-8-(6-Methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyc lopropyl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one, a Potent and Selective Pim- 1/2 Kinase Inhibitor for Hematological Malignancies.,Wang HL, Andrews K, Booker SK, Canon J, Cee VJ, Chavez F Jr, Chen Y, Eastwood H, Guerrero N, Herberich B, Hickman D, Lanman BA, Laszlo Iii J, Lee MR, Lipford JR, Mattson B, Mohr C, Nguyen Y, Norman MH, Pettus LH, Powers D, Reed AB, Rex K, Sastri C, Tamayo NA, Wang P, Winston JT, Wu B, Wu Q, Wu T, Wurz RP, Xu Y, Zhou Y, Tasker AS J Med Chem. 2019 Jan 9. doi: 10.1021/acs.jmedchem.8b01733. PMID:30624936[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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