Qi Yanan, Zhu Xinyi, Han Jingjing, Yan Yuanyuan, Cui Mengting, Hao Yanmei, Yang Lin, Dai Wenting, Wu Hongyan, Tao Yu, He Qiwei, Yu Chen, Liu Fang, Fan Fangtian
School of Pharmacy, Bengbu Medical University, Bengbu, China; Anhui Engineering Technology Research Center of Biochemical Pharmaceutical, Bengbu, China.
Department of Clinical Laboratory, School of Laboratory, Bengbu Medical University, Bengbu, China.
Eur J Pharmacol. 2025 Jun 5;996:177541. doi: 10.1016/j.ejphar.2025.177541. Epub 2025 Mar 26.
AML is the most common and lethal type of leukemia. The mutant of FLT3 kinase is the most common mutation in AML. Based on the structure analysis and deuteration modification of the cmpd 18 (CHMFL-FLT3-122), a potent and orally available FLT3 Kinase inhibitor, cmpd D6 (FH-001) was found, which demonstrated a remarkable inhibitory effect on the proliferation of FLT3 - ITD positive AML cancer cell lines. Specifically, it effectively suppressed the growth of the MV4-11 cell line (IC = 42.8 nM versus 17.1 nM). Similarly, notable inhibitory activity was observed in the MOLM-13 (IC = 20.8 nM versus 53.9 nM). More importantly, the IC of cmpd D6 to inhibit FLT3 kinase was 338.689 nM and the IC to inhibit c-KIT kinase was 3006.042 nM, which were much lower than the IC of cmpd 18 to the two kinases, indicating that cmpd D6 may effectively avoid the synthetic lethal myelosuppression toxicity caused by FLT3/c-KIT double inhibition. Pharmacokinetic experiments showed that the deuterated cmpd D6 could prolong the half-life (T = 4.333 h versus 3.646 h) and improve bioavailability (F = 42.51 % versus 35.93 %). Pharmacodynamic experiments of the three models showed that cmpd D6 (12.5 mg/kg) could significantly inhibit tumor growth compared with cmpd 18, and had no obvious toxicity. Based on the above results, cmpd D6 is a potential candidate drug for the future treatment of FLT3-ITD positive AML.
急性髓系白血病（AML）是最常见且致命的白血病类型。FLT3激酶突变是AML中最常见的突变。基于对化合物18（CHMFL - FLT3 - 122，一种强效且口服可用的FLT3激酶抑制剂）的结构分析和氘代修饰，发现了化合物D6（FH - 001），它对FLT3 - ITD阳性AML癌细胞系的增殖具有显著抑制作用。具体而言，它有效抑制了MV4 - 11细胞系的生长（IC = 42.8 nM，而之前为17.1 nM）。同样，在MOLM - 13细胞系中也观察到显著的抑制活性（IC = 20.8 nM，而之前为53.9 nM）。更重要的是，化合物D6抑制FLT3激酶的IC为338.689 nM，抑制c - KIT激酶的IC为3006.042 nM，远低于化合物18对这两种激酶的IC，表明化合物D6可能有效避免FLT3/c - KIT双重抑制导致的合成致死性骨髓抑制毒性。药代动力学实验表明，氘代化合物D6可延长半衰期（T = 4.333 h，而之前为3.646 h）并提高生物利用度（F = 42.51%，而之前为35.93%）。三种模型的药效学实验表明，与化合物18相比，化合物D6（剂量为12.5 mg/kg）可显著抑制肿瘤生长，且无明显毒性。基于上述结果，化合物D6是未来治疗FLT3 - ITD阳性AML的潜在候选药物。
