5MHQ

CCT068127 in complex with CDK2

5MHQ の概要

• エントリーDOI: 10.2210/pdb5mhq/pdb
• 分子名称: Cyclin-dependent kinase 2, (2~{R},3~{S})-3-[[9-propan-2-yl-6-(pyridin-3-ylmethylamino)purin-2-yl]amino]pentan-2-ol (3 entities in total)
• 機能のキーワード: cell cycle, inhibitor, cdk2, cdk9, cell cycle-inhibitor complex, cell cycle/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35173.82

構造登録者

Whittaker, S.R.,Barlow, C.,Martin, M.P.,Mancusi, C.,Wagner, S.,Barrie, E.,te Poele, R.,Sharp, S.,Brown, N.,Wilson, S.,Clarke, P.,Walton, M.I.,MacDonald, E.,Blagg, J.,Noble, M.E.M.,Garrett, M.D.,Workman, P. (登録日: 2016-11-25, 公開日: 2017-12-20, 最終更新日: 2025-04-09)

主引用文献

Whittaker, S.R.,Barlow, C.,Martin, M.P.,Mancusi, C.,Wagner, S.,Self, A.,Barrie, E.,Te Poele, R.,Sharp, S.,Brown, N.,Wilson, S.,Jackson, W.,Fischer, P.M.,Clarke, P.A.,Walton, M.I.,McDonald, E.,Blagg, J.,Noble, M.,Garrett, M.D.,Workman, P.
Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor.
Mol Oncol, 12:287-304, 2018

PubMed Abstract: Deregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecular and cellular effects of CCT068127, a novel inhibitor of CDK2 and CDK9. Optimized from the purine template of seliciclib, CCT068127 exhibits greater potency and selectivity against purified CDK2 and CDK9 and superior antiproliferative activity against human colon cancer and melanoma cell lines. X-ray crystallography studies reveal that hydrogen bonding with the DFG motif of CDK2 is the likely mechanism of greater enzymatic potency. Commensurate with inhibition of CDK activity, CCT068127 treatment results in decreased retinoblastoma protein (RB) phosphorylation, reduced phosphorylation of RNA polymerase II, and induction of cell cycle arrest and apoptosis. The transcriptional signature of CCT068127 shows greatest similarity to other small-molecule CDK and also HDAC inhibitors. CCT068127 caused a dramatic loss in expression of DUSP6 phosphatase, alongside elevated ERK phosphorylation and activation of MAPK pathway target genes. MCL1 protein levels are rapidly decreased by CCT068127 treatment and this associates with synergistic antiproliferative activity after combined treatment with CCT068127 and ABT263, a BCL2 family inhibitor. These findings support the rational combination of this series of CDK2/9 inhibitors and BCL2 family inhibitors for the treatment of human cancer.

PubMed: 29063678
DOI: 10.1002/1878-0261.12148

実験手法

X-RAY DIFFRACTION (1.3 Å)