(R)-CR8

Molecular glues such as (R)-CR8 induce the formation of a complex between the cyclin dependent kinase CDK12/Cyclin K and the CUL4 adaptor protein DDB1 (DNA damage binding protein 1), directly presenting CDK12/cyclin K for ubiquitination and degradation. CR8 is considered a pan-CDK inhibitor, by acting as a monovalent degrader of cyclin K. CR8 is derived from seliciclib, a CDK inhibitor with no solvent-exposed pyridine. The introduction of solvent exposure pyridine in CR8 created a new mechanism of action, highlighting the real impact of small molecular structure modifications to create innovative tools. CDKs (cyclin-dependent kinases) are serine/threonine kinases involved in a myriad of critical celullar functions. CDK12 (cyclin-dependent kinase 12)/Cyclin K plays a critical pathophysiological role in cancer and other diseases through its involvement in transcription regulation, DNA damage repair, and genomic stability. CDK12/13 regulate transcription by phosphorylating the C-terminal domain of RNA polymerase II on Ser2, regulating the expression of DNA damage response (DDR) proteins. Understanding the mechanisms underlying CDK12/Cyclin K and how its inactivation can cause genomic instability, can lead to the development of novel targeted therapies and personalized treatment strategies for patients. DDB1 (DNA damage-binding protein 1) functions as a core component of the Cullin 4 (CUL4)-based E3 ubiquitin ligase complexes. DDB1 serves as a bridge or adaptor protein which interacts with Cereblon or with DCAFs (DDB1 and CUL4-associated factors), which are ubiquitin ligase substrates. Molecular glues such as (R)-CR8 induce the formation of a complex between CDK12/Cyclin K and the CUL4 adaptor protein DDB1, directly presenting CDK12/cyclin K for ubiquitination and degradation. CR8 is considered a pan-CDK inhibitor, by acting as a monovalent degrader of cyclin K. CR8 is derived from seliciclib, a CDK inhibitor with no solvent-exposed pyridine. The introduction of solvent exposure pyridine in CR8 created a new mechanism of action, highlighting the real impact of small molecular structure modifications to create innovative tools. The development of these molecular glues and PROTACS opens new avenues in cancer therapy.