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  • Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.

Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.

Bioorganic & medicinal chemistry letters (2020-03-19)
Niall A Anderson, Jenni Cryan, Adil Ahmed, Han Dai, Grant A McGonagle, Christine Rozier, Andrew B Benowitz
ABSTRACT

Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
(S,R,S)-AHPC-Me, 95%