导读：葛微课题组在nature子刊《Leukemia》 杂志发表研究论文“« MZH29 is a novel potent inhibitor that overcomes drug resistance- FLT3 mutations in acute myeloid leukemia» （2017年）”。通过对200多个全新合成的化合物进行体外酶活性和细胞水平筛选，并对筛选到的化合物MZH29进行了体内外药效学评价及相关分子机制的研究。

       中国医学科学院基础医学研究所，“医学分子生物学国家重点实验室”的葛微课题组发现化合物MZH29对FLT3-ITD突变型急性随性白血病具有治疗作用，尤其是对FLT3-D835H/Y/V，FLT3-K663Q和FLT3-ITD-f691L等突变仍然有效。通过计算机分子模拟实验证实了MZH29对耐药突变的作用机制。本研究证实MZH29具有作为治疗FLT3突  变型急性髓性白血病的新型抑制剂。

【摘要】：More than one-third of patients with acute myeloid leukemia (AML) harbor aberrant mutations in FMS-like tyrosine kinase 3 (FLT3). Among them, the internal tandem duplication (ITD) mutation predicts poor prognosis. MZH29 is a novel FLT3 inhibitor synthesized in our laboratory that showed in cellular and kinase assays sustained inhibitory effects on wild-type and mutant FLT3, including the FLT3-ITD, FLT3-D835H/Y/V, and FLT3-K663Q mutants. More importantly, MZH29 retained its potent inhibitory effect against the FLT3-ITD/F691L mutation, a drug resistance mutation against the well-known FLT3 inhibitor, AC220. MZH29 is a type II FLT3 inhibitor that tolerated the F691L mutation in molecular docking studies. Oral administration of 10 mg/kg MZH29 caused complete tumor regression and extended survival in a mouse model of AML with less toxicity. Subsequent proteomics study revealed less proteome perturbation in the MZH29-treated group than in the AC220-treated group. MZH29 demonstrates potential and potent novel FLT3 inhibitory effects for the treatment of AML.

        相关结果已发表于《Leukemia》 杂志（2017年online），其共同第一作者为葛微课题组博士研究生许本洪，重点室葛微教授是本文的通讯作者。该研究工作得到了以下基金的支持：Novo Nordisk Union Diabetes Research Talent Fund；CAMS Initiative for Innovative Medicine（2016-I2M-1-003）; PUMC Youth Fund, and the Fundamental Research Funds for the Central Universities (3332015020)。