Home PROTAC Molecule CDK/PROTAC
Utilizing heterobifunctional proteolysis-targeting chimera (PROTAC) compounds for targeted protein degradation, a strategy that recruits E3 ligase machinery to a specific protein, is increasingly gaining traction as a compelling pharmacologic approach. Typically derived from existing inhibitors, PROTAC compounds require thorough assessment of selectivity to comprehend both on-target and off-target degradation. In this study, we present a comprehensive kinetic degradation analysis of TL12-186, a pan-kinase PROTAC, applied to 16 members of the cyclin-dependent kinase (CDK) family. Each CDK family member was intrinsically labeled with the 11-amino-acid HiBiT peptide, enabling real-time luminescent monitoring of degradation within live cells. Employing this methodology, we observed notable differences and patterns in kinetic degradation rates, potencies, and Dmax values across the CDK family members. Analysis of the responses revealed that the majority of CDKs underwent rapid and nearly complete degradation, whereas all cell cycle-associated CDKs (1, 2, 4, and 6) exhibited multimodal and partial degradation.
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