6MT0
Crystal structure of human Pim-1 kinase in complex with a quinazolinone-pyrrolodihydropyrrolone inhibitor
Summary for 6MT0
| Entry DOI | 10.2210/pdb6mt0/pdb |
| Descriptor | Serine/threonine-protein kinase pim-1, 3-(1-methylcyclopropyl)-2-[(1-methylcyclopropyl)amino]-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 | serine/threonine protein kinase, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 33652.09 |
| Authors | Mohr, C. (deposition date: 2018-10-18, release date: 2019-01-16, Last modification date: 2024-03-13) |
| Primary citation | Wang, H.L.,Andrews, K.L.,Booker, S.K.,Canon, J.,Cee, V.J.,Chavez Jr., F.,Chen, Y.,Eastwood, H.,Guerrero, N.,Herberich, B.,Hickman, D.,Lanman, B.A.,Laszlo 3rd., J.,Lee, M.R.,Lipford, J.R.,Mattson, B.,Mohr, C.,Nguyen, Y.,Norman, M.H.,Pettus, L.H.,Powers, D.,Reed, A.B.,Rex, K.,Sastri, C.,Tamayo, N.,Wang, P.,Winston, J.T.,Wu, B.,Wu, Q.,Wu, T.,Wurz, R.P.,Xu, Y.,Zhou, Y.,Tasker, A.S. Discovery of ( R)-8-(6-Methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4- b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3 H)-one, a Potent and Selective Pim-1/2 Kinase Inhibitor for Hematological Malignancies. J. Med. Chem., 62:1523-1540, 2019 Cited by PubMed Abstract: Pim kinases are a family of constitutively active serine/threonine kinases that are partially redundant and regulate multiple pathways 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 phosphorylation in KMS-12-BM multiple myeloma tumors for 16 h postdose. In a 2-week mouse xenograft model, daily dosing of compound 28 resulted in 33% tumor regression at 100 mg/kg. PubMed: 30624936DOI: 10.1021/acs.jmedchem.8b01733 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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