2. Academic Validation
  3. Discovery and characterisation of VPRBP/DCAF1 kinase inhibitor analogues as microtubular destabilising agents with potent anti-myeloma activity

Discovery and characterisation of VPRBP/DCAF1 kinase inhibitor analogues as microtubular destabilising agents with potent anti-myeloma activity

  • Mol Cancer Ther. 2025 Nov 4. doi: 10.1158/1535-7163.MCT-25-0306.
Olivia Susanto 1,  Emily Gruber 2,  Cheng Mun Wun 3,  Rheana L Franich 4,  Xiao Ma 5,  Zahra Sabouri-Thompson 1,  Zoe J Porter 5,  Heather C Murray 6,  Leonie A Cluse 7,  Belinda Maher 1,  Daniella Brasacchio 8,  Benjamin P Martin 7,  Peter J Fraser 2,  Iva Nikolic 9,  Gisela Mir Arnau 10,  Jarrod J Sandow 11,  Kaylene J Simpson 4,  Nicole M Verrills 6,  Ricky W Johnstone 2,  Philip E Thompson 12,  Lev M Kats 4,  Jake Shortt 8
Affiliations

Affiliations

  • 1 Monash University, Clayton, VIC, Australia.
  • 2 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 3 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • 4 Peter MacCallum Cancer Centre, Melbourne, Australia.
  • 5 Monash University, Parkville, VIC, Australia.
  • 6 University of Newcastle Australia, Callaghan, Australia.
  • 7 Peter MacCallum Cancer Centre, East Melbourne, Australia.
  • 8 Monash University, Clayton, Victoria, Australia.
  • 9 onko-innate, Australia.
  • 10 Vall d'Hebron Institute of Oncology, Barcelona, Spain.
  • 11 Walter and Eliza Hall Institute of Medical Research, Australia.
  • 12 Monash University, Melbourne, Australia.
PMID: 41185616 DOI: 10.1158/1535-7163.MCT-25-0306
Abstract

Multiple myeloma is a plasma cell malignancy that is susceptible to drugs targeting protein homeostasis such as thalidomide analogues and Proteasome inhibitors. Thalidomide analogues modulate the activity of DDB1/CUL4 E3-ligase complexes to perturb substrate recognition and proteasomal degradation thereof. We hypothesised that the cellular pool of DDB1/CUL4 associated factors (DCAFs) may mediate Other essential plasma cell processes and offer new targets for therapeutic intervention. Unbiased genetic screening identified DCAF1 (also known as Vpr-binding protein; VPRBP) as essential for myeloma cell survival with a multidomain structure offering several distinct opportunities for drug development. Utilising B32B3, a previously disclosed DCAF1 kinase inhibitor as a template, we developed a series of analogues with enhanced anti-myeloma potency. As anti-myeloma 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 analogues as microtubular destabilising agents with potential DCAF1 kinase independent properties and in vivo efficacy in multiple myeloma and lymphoma.

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