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

abstract

  • 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 13 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 13 significantly improved survival. Subsequent optimization efforts led to the development of SR-C-107 (R), which exhibited strong activity against AML both at the cellular level (CC50(MOLM-13): 1.25 0.18 M; CC50(MV4-11): 0.81 0.15 M) and in vivo. These findings establish SR-C-107 (R) as a compelling candidate for AML treatment and lay the groundwork for the development of next-generation AML inhibitors.

published proceedings

  • J Med Chem

author list (cited authors)

  • Guo, X. S., Atla, S., Nyalata, S., Alugubelli, Y. R., Chen, P., Xu, S., & Liu, W. R.

complete list of authors

  • Guo, Xuejiao Shirley||Atla, Sandeep||Nyalata, Satyanarayana||Alugubelli, Yugendar R||Chen, Peng-Hsun Chase||Xu, Shiqing||Liu, Wenshe Ray