Characterization of a novel therapeutic agent exhibiting potent anti-myeloma activity by destabilising microtubules.

Multiple myeloma (MM) is the second most common haematological malignancy, accounting for 1% of all cancers and shows increasing incidence worldwide. However, it remains an incurable disease with most patients developing therapeutic resistance and succumbing to refractory disease. It is therefore crucial to identify novel drug targets in MM to improve patient outcomes. In our study, we propose a novel compound that exhibits therapeutic efficacy across various models and insights into its mechanism. Current MM therapeutic strategies target the ubiquitin-proteasome system (UPS) through immunomodulatory drugs or proteosome inhibitors. Hence, we utilised B32B3, a purported DCAF1 (E3 ligase recognition subunit) modulator, as a template to generate a chemical library which was screened for therapeutic efficacy in MM cell lines. The selected lead derivative, Vpr8, showed >40x increased potency compared to B32B3 with potent anti-tumour effects both in vitro and in vivo. Drug-treated mice bearing MM xenografts showed delayed disease progression and a survival advantage relative to vehicle controls. Treatment of primary human MM samples showed increased cell death in malignant cells (CD38+) compared to normal haematopoietic cells (CD45+). A genome-wide CRISPR screen for genes that modulate the sensitivity of MM cells to Vpr8 treatment was conducted and identified genes regulating microtubule stability and G2/M transition. Subsequent mechanistic studies confirmed that Vpr8 promotes microtubule depolymerisation and spindle abnormalities. Overall, our findings identify a novel anti-cancer agent and gives insight into the potential use of B32B3 analogues as an alternate therapeutic strategy in MM. Multiple myeloma (MM) is the second most common haematological malignancy, accounting for 1% of all cancers and shows increasing incidence worldwide. However, it remains an incurable disease with most patients developing therapeutic resistance and succumbing to refractory disease. It is therefore crucial to identify novel drug targets in MM to improve patient outcomes. In our study, we propose a novel compound that exhibits therapeutic efficacy across various models and insights into its mechanism. Current MM therapeutic strategies target the ubiquitin-proteasome system (UPS) through immunomodulatory drugs or proteosome inhibitors. Hence, we utilised B32B3, a purported DCAF1 (E3 ligase recognition subunit) modulator, as a template to generate a chemical library which was screened for therapeutic efficacy in MM cell lines. The selected lead derivative, Vpr8, showed >40x increased potency compared to B32B3 with potent anti-tumour effects both in vitro and in vivo. Drug-treated mice bearing MM xenografts showed delayed disease progression and a survival advantage relative to vehicle controls. Treatment of primary human MM samples showed increased cell death in malignant cells (CD38+) compared to normal haematopoietic cells (CD45+). A genome-wide CRISPR screen for genes that modulate the sensitivity of MM cells to Vpr8 treatment was conducted and identified genes regulating microtubule stability and G2/M transition. Subsequent mechanistic studies confirmed that Vpr8 promotes microtubule depolymerisation and spindle abnormalities. Overall, our findings identify a novel anti-cancer agent and gives insight into the potential use of B32B3 analogues as an alternate therapeutic strategy in MM.