Charting and Disrupting the Gene-Regulatory Function of CDK6

The proposal Charting and Disrupting the Gene-Regulatory Function of CDK6 outlines a multi- disciplinary approach to elucidate the role of the cyclin dependent kinase 6 (CDK6) in sustaining leukemic gene-regulatory circuits. Initially, CDK6 and the closely related CDK4 have mostly been implicated in controlling how and when cells divide. Deregulation of this regulatory checkpoint has often been associated with aberrant cell cycle progression and cellular proliferation found in cancer. Small molecule inhibitors that block isolated functions of CDK4 and CDK6 have thus been innovated, clinically approved and are successfully used in the treatment of certain cancer types. Recently, CDK6 has also been shown to directly control gene regulation and gene activity. Interestingly, this role is specific for CDK6 over CDK4. Among others, it has been implicated in sustaining transcriptional networks in different blood cancers as well as blood cancer stem cells. Intriguingly, pharmacologic interference with the gene-regulatory role of CDK6 would thus represent a novel therapeutic approach in treating aberrant transcriptional programs driving leukemia pathogenesis. However, in contrast to the role of CDK6 in promoting cell cycle progression, the gene-regulatory function of CDK6 cannot be blocked with currently available small molecule drugs. This is due to the fact that CDK6 does not influence gene regulation via its enzymatic function but rather by acting as a recruitment factor for downstream transcriptional effectors. This lack of chemical tractability not only stalls translational development but also severely limits our understanding of the mechanistic basis of gene-regulation executed by CDK6. Thus, we hypothesize that novel inhibitors that would be capable of blocking all associated functions of CDK6 would not only have potentially far reaching therapeutic implications but would also significantly improve our understanding of the gene-regulatory circuits controlled by CDK6. To that goal, we propose to create small molecules that can hijack effectors of the cellular protein clearance system to induce the immediate and specific degradation of CDK6. Based on the generalizable approach of phthalimide conjugation, we thus propose to create bifunctional small molecules that will modulate the activity of the E3 ligase receptor cereblon in a targeted manner in order to induce the proteasomal degradation of CDK6. We propose to deploy these pharmacologic degraders to probe the gene-regulatory function of CDK6 in leukemia cell lines and primary patient samples by measuring implications of acute CDK6 loss on global chromatin assembly, accessibility and gene activity. Moreover, we will assay the therapeutic potential of targeted CDK6 degradation in vivo in primary AML derived xenografts.

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