6MT0

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

6MT0 の概要

• エントリーDOI: 10.2210/pdb6mt0/pdb
• 分子名称: 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)
• 機能のキーワード: serine/threonine protein kinase, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33652.09

構造登録者

Mohr, C. (登録日: 2018-10-18, 公開日: 2019-01-16, 最終更新日: 2024-03-13)

主引用文献

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

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: 30624936
DOI: 10.1021/acs.jmedchem.8b01733

実験手法

X-RAY DIFFRACTION (2.2 Å)