摘要：SummaryDespite much progress in developing better drugs, many patients with acute myeloid leukemia (AML) still die within a year of diagnosis. This is partly because it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Overcoming this block should allow for the identification of therapies that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify compounds that stimulate differentiation in genetically diverse AML cell lines. Lead compounds were shown to decrease tumor burden and to increase survivalin vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a function for tubulin disruptors in causing differentiation of AML cells.Graphical abstractDisplay OmittedHighlights•Cancer treatments usually focus on killing rapidly growing cells•We focused on differentiating cancer cells independent of the driver mutation•We identified tubulin as the drug target•This work illustrates how phenotypic screening can identify unique drug targetsChemistry; Biological sciences; Molecular biology; Molecular medicine; Cancer
