Discovery and Characterization of VPRBP/DCAF1 Kinase Inhibitor Analogs as Microtubular Destabilizing Agents with Potent Antimyeloma Activity

Abstract Multiple myeloma is a plasma cell malignancy that is susceptible to drugs targeting protein homeostasis such as thalidomide analogs and proteasome inhibitors. Thalidomide analogs modulate the activity of DDB1/CUL4 E3–ligase complexes to perturb substrate recognition and proteasomal degradation thereof. We hypothesized that the cellular pool of DDB1/CUL4-associated factors (DCAF) may mediate other essential plasma cell processes and offer new targets for therapeutic intervention. Unbiased genetic screening identified DCAF1 (also known as viral protein R–binding protein) as essential for myeloma cell survival with a multidomain structure, offering several distinct opportunities for drug development. Utilizing B32B3, a previously disclosed DCAF1 kinase inhibitor as a template, we developed a series of analogs with enhanced antimyeloma potency. As antimyeloma activity did not associate with dephosphorylation of known DCAF1 kinase substrates, we correlated drug-induced cellular phenotypes with whole-genome CRISPR/Cas9 resistance screening to further define mechanistic activity. These studies identified B32B3 analogs as microtubular destabilizing agents with potential DCAF1 kinase–independent properties and in vivo efficacy in multiple myeloma and lymphoma.