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

Susanto, O; Gruber, E; Wun, CM; Franich, RL; Ma, X; Sabouri-Thompson, Z; Porter, ZJ; Murray, HC; Cluse, LA; Maher, B; Brasacchio, D; Martin, BP; Fraser, PJ; Nikolic, I; Mir Arnau, G; Sandow, JJ; Simpson, KJ; Verrills, NM; Johnstone, RW; Thompson, PE; Kats, LM; Shortt, J

Author(s): Susanto, O; Gruber, E; Wun, CM; Franich, RL; Ma, X; Sabouri-Thompson, Z; Porter, ZJ; Murray, HC; Cluse, LA; Maher, B; Brasacchio, D; Martin, BP; Fraser, PJ; Nikolic, I; Mir Arnau, G; Sandow, JJ; Simpson, KJ; Verrills, NM; Johnstone, RW; Thompson, PE; Kats, LM; Shortt, J;
Details: Publication Year 2026-03-02,Volume 25,Issue #3,Page 416-434
Journal Title: Molecular Cancer Therapeutics
Publication Type: Mar 2
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.
Publisher: AACR
Keywords: Humans; *Multiple Myeloma/drug therapy/pathology/metabolism/genetics; Animals; *Protein Kinase Inhibitors/pharmacology/chemistry; Mice; Cell Line, Tumor; Xenograft Model Antitumor Assays; *Antineoplastic Agents/pharmacology; Drug Discovery; Protein Serine-Threonine Kinases; Ubiquitin-Protein Ligases
Research Division(s): Structural Biology
PubMed ID: 41185616
Publisher's Version: https://doi.org/10.1158/1535-7163.Mct-25-0306
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-03-16 01:38:22

Last Modified: 2026-03-16 01:52:35