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DCAF1 interacting partners in myeloma cells

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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Multiple Myeloma

SUBMITTER: Laura Dagley

LAB HEAD: Associate Professor Lev Kats

PROVIDER: PXD066365 | Pride | 2025-10-06

REPOSITORIES: Pride

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	P3915_01_24_1_4279.d.zip	Other
	P3915_02_24_1_4283.d.zip	Other
	P3915_03_24_1_4287.d.zip	Other
	P3915_04_24_1_4280.d.zip	Other
	P3915_05_24_1_4284.d.zip	Other

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

Project description: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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CRL4(CRBN) ubiquitin ligase profiling

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CRL4(CRBN) ubiquitin ligase profiling

Project description:In the 1950s the drug thalidomide administered as a sedative to pregnant women led ot the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and ist IMiD derivatives recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4(CRBN)) ubiquitin ligase. Through an unbiased screen we identify the homeobox trranscription factor MEIS2 as an endogenous substrate of CRL4(CRBN). By definition, a specific target of CRL4(CRBN) is expected to have a very low intensity on negative control arrays (E1_E2), (E1_CRBN), (E1_E2_Cdt2), (E1_E2_Cdt2_revlimid), (E1_E2_Cdt2_CSN) or with CRL4(CRBN) in presence of inhibitor (E1_E2_CRBN_revlimid) and high intensity on arrays with CRL4(CRBN) (E1_E2_CRBN) or CRL4(CRBN) in presence of CSN (E1_E2_CRBN_CSN) Accordingly 16 protein microarrays were subjected to in vitro ubiquitylation using the following enzyme combinations: 3x Uba1+UbcH5a; 2x Uba1+UbcH5a+CRL4(DDB2); 3x Uba1+UbcH5a+CRL4(CRBN); 2x Uba1+UbcH5a+CRL4(CRBN)+lenalidomide; 2x Uba1+UbcH5a+CRL4(CRBN)+CSN; 2x Uba1+UbcH5a+CRL4(Cdt2); 1x Uba1+UbcH5a+CRL4(Cdt2)+CSN; 1x Uba1+UbcH5a+CRL4(Cdt2)+lenalidomide

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