The application of artificial intelligence (AI) has been considered as a revolutionary change in drug discovery and development. In 2020, AlphaFold computer program predicted protein structures for the whole human...
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.
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