Researchers identified Unc-51 like kinase 3 as a primary contributor to autophagy and cell survival in multiple myeloma, according to a study published in Nature Communications. Analysis of RNA sequencing data taken from 813 CD138-positive patient cells across various disease stages revealed an autophagy gene signature. Within that profile, elevated ULK3 expression was strongly associated with disease progression. Functional experiments showed that ULK3 supports myeloma cell survival directly through the ULK-ATG13-FIP200 complex.
Teams at the H. Lee Moffitt Cancer Center and Research Institute developed two small-molecule kinase inhibitors, named SG3-014 and MA9-060, to block the enzyme. Both compounds demonstrated nanomolar potency against ULK3, and researchers confirmed physical binding through co-crystallization experiments. In animal testing, pharmacologic inhibition reduced multiple myeloma burden, prolonged survival, and mitigated disease-related bone damage, even though the compounds showed multikinase activity.
Experiments on drug resistance showed that MA9-060 enhanced myeloma cell sensitivity to proteasome inhibitors. The team confirmed this response ex vivo in primary patient tissue samples, noting that cells with high ULK3 expression responded most strongly. Multiple myeloma patients often relapse with refractory disease despite initial treatment with proteasome inhibitors, prompting the researchers to recommend ULK3-directed kinase inhibition as a therapeutic strategy for newly diagnosed and refractory cases.
Data collection relied on the ORIEN Avatar Project alongside Aster Insights and the Total Cancer Care protocol. Structural work took place at Brookhaven National Laboratory using the NYX beamline 19-ID at the National Synchrotron Light Source II. Authors Harshani R. Lawrence, Nicholas J. Lawrence, Conor C. Lynch, and Marilena Tauro hold patents on ULK3 inhibitors under US Patent 12,391,676 and international application WO2024035771. Grant funding supported the study through the National Cancer Institute, the Pentecost Family Myeloma Research Center, and the Leukemia & Lymphoma Society.
