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Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Inhibitors of CDK8 for the Treatment of Cancer
- Source :
- Journal of Medicinal Chemistry; April 2023, Vol. 66 Issue: 8 p5439-5452, 14p
- Publication Year :
- 2023
-
Abstract
- Cyclin-dependent kinase 8 (CDK8), as a kinase subunit of the Mediator complex, is involved in the regulation of RNA polymerase II-mediated transcription, thereby modulating multiple signaling pathways and multiple transcription factors involved in oncogenic control. CDK8 deregulation has been implicated in human diseases, particularly in acute myeloid leukemia (AML) and advanced solid tumors, where it has been reported as a putative oncogene. Here, we report the successful optimization of an azaindole series of CDK8 inhibitors that were identified and further progressed through a structure-based generative chemistry approach. In several optimization cycles, we improved in vitro microsomal stability, kinase selectivity, and in vivo pharmacokinetic profile cross-species, leading to the discovery of compound 23, which demonstrated robust tumor growth inhibition in multiple in vivo efficacy models after oral administration.
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Volume :
- 66
- Issue :
- 8
- Database :
- Supplemental Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Periodical
- Accession number :
- ejs62759063
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.2c01718