CR8 is a small molecule inhibitor of cyclin-dependent kinases [1
]. It is structurally related to seliciclib
(roscovitine). This entry is for the R
isomer, which is more inhibitory at glycogen synthase kinase (GSK-3α/β) than the S
isomer. Both isomers are equipotent across CDK1, 2, 5, 7, and 9.
(R)-CR8 has been shown to act as a molecular glue degrader that depletes cyclin K [2
], thus behaving as a functional CDK inhibitor. (R)-CR8 binding to CDK12 induces formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1 which presents cyclin K for ubiquitination and degradation. Of the >8,000 proteins assessed by quantitative proteome-wide mass spectrometry, cyclin K was the only one that was consistently decreased in abundance in response to (R)-CR8 exposure.