title: MZH29 is a novel potent inhibitor that overcomes drug resistance FLT3 mutations in acute myeloid leukemia.
abstract: 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 that 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.
authors: National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors: B
authors: 0000-0002-5331-3102
authors: B
authors: Xu
authors: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang, China.
authors: Y
authors: Y
authors: Zhao
authors: National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors: X
authors: X
authors: Wang
authors: Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang, China.
authors: P
authors: P
authors: Gong
authors: National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China.
authors: W
authors: 0000-0002-9907-512X
authors: W
authors: Ge
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020440:Gene Duplication; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D020080:Tandem Repeat Sequences; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C000623151:MZH29 compound; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D051941:fms-Like Tyrosine Kinase 3