Discovery and Characterization of VPRBP/DCAF1 Kinase Inhibitor Analogs as Microtubular Destabilizing Agents with Potent Antimyeloma Activity
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.
Authors
- Daniella Brasacchio (ORCID: https://orcid.org/0000-0001-5956-9611)
- Olivia Susanto (ORCID: https://orcid.org/0000-0001-6360-1952)
- Philip Evan Thompson (ORCID: https://orcid.org/0000-0002-5910-7625)
- Iva Nikolić (ORCID: https://orcid.org/0000-0002-0141-5975)
- Zoe J. Porter (ORCID: https://orcid.org/0000-0002-9736-7540)
- Kaylene J. Simpson (ORCID: https://orcid.org/0000-0001-9136-1781)
- Emily Gruber (ORCID: https://orcid.org/0000-0001-5990-036X)
- Ricky W. Johnstone (ORCID: https://orcid.org/0000-0001-7053-9237)
- Lev M. Kats (ORCID: https://orcid.org/0000-0001-8742-8138)
- Rheana Franich (ORCID: https://orcid.org/0000-0001-9784-4936)
- Jake Shortt (ORCID: https://orcid.org/0000-0003-3185-6488)
- Cheng Mun Wun (ORCID: https://orcid.org/0000-0001-6740-3881)
- Leonie A. Cluse (ORCID: https://orcid.org/0000-0001-8613-0508)
- Benjamin P. Martin (ORCID: https://orcid.org/0009-0000-8986-1509)
- Nicole M. Verrills (ORCID: https://orcid.org/0000-0002-7894-0137)
- Belinda Maher (ORCID: https://orcid.org/0000-0002-8900-6876)
- Jarrod J. Sandow (ORCID: https://orcid.org/0000-0001-5684-8236)
- Heather C. Murray (ORCID: https://orcid.org/0000-0001-8953-3708)
- Peter Fraser (ORCID: https://orcid.org/0009-0001-6955-4955)
- Zahra Sabouri-Thompson (ORCID: https://orcid.org/0009-0003-9980-5887)
- Xiao Ma (ORCID: https://orcid.org/0000-0002-9842-9045)
- Gisela Mir Arnau (ORCID: https://orcid.org/0009-0007-1180-5604)
Institutions
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Peter MacCallum Cancer Centre (AU)
- Hunter Medical Research Institute (AU)
- Monash Health (AU)
- Innate Pharma (France) (FR)
- Vall d'Hebron Institute of Oncology (ES)
- Monash University (AU)
- University of Newcastle Australia (AU)
Publication Details
- Journal
- Molecular Cancer Therapeutics
- Published
- 2025-11-03
- DOI
- https://doi.org/10.1158/1535-7163.mct-25-0306
- Primary Topic
- Multiple Myeloma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00