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 (CC_{50 (MOLM-13)}: 1.25 ± 0.18 μM; CC_50 (MV4-11): 0.81 ± 0.15 μM) 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.

中文翻译：

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优先考虑 11-19-白血病抑制剂作为急性髓性白血病的口服候选药物


急性髓性白血病 （AML） 是第二普遍和致命的白血病形式。携带致癌 MLL 重排的 AML 细胞的生长依赖于含有 YEATS 结构域的蛋白质 ENL。已经开发了许多靶向 ENL 的小分子抑制剂。为了优先考虑这些抑制剂进行体内研究，引入了 NanoBRET 系统来评估它们的细胞通透性和效力。该筛选确定抑制剂 13 是一个有前途的候选者。该抑制剂对 MLL 融合白血病细胞系具有显着的代谢稳定性和有效的抗增殖作用。在 AML 异种移植小鼠中，抑制剂 13 显著提高了生存率。随后的优化工作导致了 SR-C-107 （R） 的开发，它在细胞水平上表现出很强的抗 AML 活性 （CC_{50 （MOLM-13）：}1.25 ± 0.18 μM;CC_{50 （MV4-11）：}0.81 ± 0.15 μM）和体内。这些发现确立了 SR-C-107 （R） 是 AML 治疗的令人信服的候选药物，并为开发下一代 AML 抑制剂奠定了基础。