Pharmacologic and genetic inhibition of UBE2N suppresses the function and viability of MDS/AML cells lines and patient samples. A commercially available and a novel compound has been identified.

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are myeloid malignancies that originate from mutant hematopoietic stem and progenitor cells (HSPCs), known as leukemic stem and progenitor cells (LSPCs). Treatment options for MDS/AML patients remain minimal and often toxic, leading to unfavorable outcomes. Identifying therapeutic targets to eliminate LSPCs is crucial for improving patient prognosis. Our technology targets UBE2N, an enzyme in the ubiquitination process, to combat high-risk MDS and AML. UBE2N inhibition offers a novel therapeutic approach by selectively targeting LSPCs without significantly affecting normal HSPCs. Through high-throughput screens, in silico modeling, and cell based cytotoxicity assays, we have identified covalent small molecule inhibitors that selectively bind to UBE2N’s catalytic residue, thus inhibiting UBE2N's function.

A novel therapeutic approach which promises to improve survival outcome of MDS/AML patients and could be implicated in solid tumors.

* Targeted therapy for pediatric/adult AML and MDS * Extension of standard of care (SOC) treatments for MDS/AML * Potential treatment for various solid tumors and inflammation * Reduced toxicity compared to other ubiquitination pathway inhibitors

* Annual incidence of over 20,000 new AML cases and 15,000-20,000 new MDS cases reported in the U.S. * Approximately one-third of MDS patients progress to AML,

Daniel Starczynowski, PhD