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Homolog-selective degradation as a strategy to probe the function of CDK6 in AML

ABSTRACT: The design of selective small-molecules is often stymied by similar ligand binding pockets. Here we report the first cyclin-dependent kinase 6 (CDK6) degrader, BSJ-03-123, that uses phthalimide-conjugation to exploit protein-interface determinants to achieve proteome-wide degradation selectivity. Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and coupling acute degradation with transcriptomics and phosphoproteomics enabled dynamic mapping of the immediate role of CDK6 in coordinating signaling and transcription.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116187 | GEO | 2018/11/20

REPOSITORIES: GEO

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CDK6 degradation is counteracted by p16INK4A and p18INK4C in AML

Project description:Cyclin-dependent kinase 6 (CDK6) represents a novel therapeutic target for the treatment of certain subtypes of acute myeloid leukemia (AML). CDK4/6 kinase inhibitors have been widely studied in many cancer types and their effects may be limited by primary and secondary resistance mechanisms. CDK4/6 degraders, which eliminate kinase dependent and kinase independent effects, have been suggested as alternative therapeutic option. We show that efficacy of the CDK6 specific protein degrader BSJ-03-123 varies among AML subtypes and depends on low expression of the INK4 proteins p16INK4A and p18INK4C. INK4 protein levels are significantly elevated in MLL-AF9+ compared to AML1-ETO+ cells, contributing to the different CDK6 degradation efficacy. We demonstrate that CDK6 complexes containing p16INK4A or p18INK4C are protected from BSJ-mediated degradation and that INK4 levels define the proliferative response to CDK6 degradation. These findings define INK4 proteins as predictive marker for CDK6 degradation – targeted therapies in AML.

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Homolog-selective degradation as a strategy to probe the function of CDK6 in AML

Project description:Homolog-selective degradation as a strategy to probe the function of CDK6 in AML

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RNA-seq data from VavCre;Jak2+/+; Cdk6+/+, VavCre;Jak2V617F; Cdk6+/+, VavCre;Jak2V617F; Cdk6-/-, VavCre; Jak2+/+; Cdk6-/- murine bone marrow LSK cells and VavCre; Jak2V617F; Cdk6+/+ Palbociclib treated murine bone marrow LSK cells

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