Unc-51 like kinase 3 (ULK3) contributes to autophagy and cell survival in multiple myeloma.

Despite effective therapies such as proteasome inhibitors, multiple myeloma (MM) patients relapse with refractory disease. Analysis of RNA sequencing data from CD138 + MM patient cells (n = 813) across disease stages identifies an autophagy gene signature. Particularly elevated ULK3 expression is strongly associated with disease progression. Functional studies reveal that ULK3 supports MM cell survival via the ULK-ATG13-FIP200 complex. We generate small-molecule kinase inhibitors (SG3-014/MA9-060) exhibiting nanomolar potency against ULK3, with binding confirmed by co-crystallization. While exhibiting multikinase activity, pharmacologic targeting reduces MM burden in vivo, improves survival, and mitigates MM-associated bone disease. Here, we also show that MA9-060 enhances sensitivity to proteasome inhibitors in resistant MM cells, with effects confirmed ex vivo in primary patient samples, particularly those with high ULK3 expression. These findings implicate ULK3-associated autophagy in MM progression and support further evaluation of ULK3-directed kinase inhibition as a therapeutic strategy in newly diagnosed and refractory MM.