Halogen bonds form the basis for selective P-TEFb inhibition by DRB
- PMID: 20851342
- DOI: 10.1016/j.chembiol.2010.07.012
Halogen bonds form the basis for selective P-TEFb inhibition by DRB
Abstract
Cdk9, the kinase of the positive transcription elongation factor b, is required for processive transcription elongation by RNA polymerase II. Cdk9 inhibition contributes to the anticancer activity of many Cdk inhibitors under clinical investigation and hence there is interest in selective Cdk9 inhibitors. DRB (5,6-dichlorobenzimidazone-1-β-D-ribofuranoside) is a commonly used reagent for Cdk9 inhibition in cell biology studies. The crystal structures of Cdk9 and Cdk2 in complex with DRB reported here describe the molecular basis for the DRB selectivity toward Cdk9. The DRB chlorine atoms form halogen bonds that are specific for the Cdk9 kinase hinge region. Kinetic and thermodynamic experiments validate the structural findings and implicate the C-terminal residues of Cdk9 in contributing to the affinity for DRB. These results open the possibility to exploit halogen atoms in inhibitor design to specifically target Cdk9.
Copyright © 2010 Elsevier Ltd. All rights reserved.
Similar articles
-
Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity.J Med Chem. 2013 Feb 14;56(3):660-70. doi: 10.1021/jm301495v. Epub 2013 Jan 29. J Med Chem. 2013. PMID: 23252711 Free PMC article.
-
The CDK9 tail determines the reaction pathway of positive transcription elongation factor b.Structure. 2012 Oct 10;20(10):1788-95. doi: 10.1016/j.str.2012.08.011. Epub 2012 Sep 6. Structure. 2012. PMID: 22959624 Free PMC article.
-
Cyclin-dependent kinase 9 is required for tumor necrosis factor-alpha-stimulated matrix metalloproteinase-9 expression in human lung adenocarcinoma cells.J Biol Chem. 2005 Jan 14;280(2):1103-11. doi: 10.1074/jbc.M406293200. Epub 2004 Nov 4. J Biol Chem. 2005. PMID: 15528190
-
CDK9: a signaling hub for transcriptional control.Transcription. 2019 Apr;10(2):57-75. doi: 10.1080/21541264.2018.1523668. Epub 2018 Oct 11. Transcription. 2019. PMID: 30227759 Free PMC article. Review.
-
Pharmacological targeting of CDK9 in cardiac hypertrophy.Med Res Rev. 2010 Jul;30(4):646-66. doi: 10.1002/med.20172. Med Res Rev. 2010. PMID: 19757441 Review.
Cited by
-
Chemo-Phosphoproteomic Profiling with ATR Inhibitors Berzosertib and Gartisertib Uncovers New Biomarkers and DNA Damage Response Regulators.Mol Cell Proteomics. 2024 Jun 15;23(8):100802. doi: 10.1016/j.mcpro.2024.100802. Online ahead of print. Mol Cell Proteomics. 2024. PMID: 38880245 Free PMC article.
-
Structure-guided design and cloning of peptide inhibitors targeting CDK9/cyclin T1 protein-protein interaction.Front Pharmacol. 2024 May 14;15:1327820. doi: 10.3389/fphar.2024.1327820. eCollection 2024. Front Pharmacol. 2024. PMID: 38808256 Free PMC article.
-
Synthesis of 1,3,4-Thiadiazole Derivatives and Their Anticancer Evaluation.Int J Mol Sci. 2023 Dec 14;24(24):17476. doi: 10.3390/ijms242417476. Int J Mol Sci. 2023. PMID: 38139304 Free PMC article.
-
Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers.J Med Chem. 2023 Dec 14;66(23):15629-15647. doi: 10.1021/acs.jmedchem.3c01233. Epub 2023 Nov 15. J Med Chem. 2023. PMID: 37967851 Free PMC article.
-
PGC-1α senses the CBC of pre-mRNA to dictate the fate of promoter-proximally paused RNAPII.Mol Cell. 2023 Jan 19;83(2):186-202.e11. doi: 10.1016/j.molcel.2022.12.022. Mol Cell. 2023. PMID: 36669479 Free PMC article.
Publication types
MeSH terms
Substances
Associated data
- Actions
- Actions
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous