Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Orally Available Drug Candidates for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the second most prevalent and fatal form of leukemia. The growth of AML cells harboring oncogenic MLL rearrangements relies on the YEATS domain-containing protein ENL. Many small molecule inhibitors targeting ENL have been developed. To prioritize these inhibitors for in vivo studies, a NanoBRET system was introduced to evaluate their cellular permeability and potency. This screening identified inhibitor as a promising candidate. This inhibitor has remarkable metabolic stability and potent antiproliferative effects on MLL-fusion leukemia cell lines. In AML-xenografted mice, inhibitor significantly improved survival. Subsequent optimization efforts led to the development of , which exhibited strong activity against AML both at the cellular level (: 1.25 ± 0.18 μM; : 0.81 ± 0.15 μM) and in vivo. These findings establish as a compelling candidate for AML treatment and lay the groundwork for the development of next-generation AML inhibitors.