In this work, we identify pevonedistat (PEV), a first-in-class inhibitor of neddylation recently approved for the treatment of high-risk myelodysplastic syndromes (HR-MDS), as synergistically cytotoxic with TOP1 inhibitors by high-throughput screens in human colorectal carcinoma cells. The gene discussed is TOP1; the disease is myelodysplastic syndrome.