1. G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia
- Author
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Jong Sung Koh, Kim Jung-Ho, Jung Keun Kim, Se Won Kim, Dong Sik Jung, Jungmi Lee, Hee Kyu Lee, Sang Yeop Lee, Choi Jang-Sik, In Yong Lee, Park Sung-Ho, Jaekyoo Lee, Hong Woo Kim, Hae-Jun Hwang, Jan Cools, and Ho-Juhn Song
- Subjects
Myeloid ,Pyridones ,Immunology ,Mutation, Missense ,Drug resistance ,Biology ,Pharmacology ,Biochemistry ,Mice ,fluids and secretions ,hemic and lymphatic diseases ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Protein Kinase Inhibitors ,Myeloid Neoplasia ,Myeloid leukemia ,hemic and immune systems ,Drug Synergism ,Cell Biology ,Hematology ,medicine.disease ,Xenograft Model Antitumor Assays ,Protein Structure, Tertiary ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Pyrimidines ,fms-Like Tyrosine Kinase 3 ,Drug Resistance, Neoplasm ,Fms-Like Tyrosine Kinase 3 ,embryonic structures ,Mutant Proteins ,Bone marrow ,FLT3 Inhibitor ,K562 Cells ,K562 cells - Abstract
Aberrant activations of Fms-like tyrosine receptor kinase (FLT) 3 are implicated in the pathogenesis of 20% to 30% of patients with acute myeloid leukemia (AML). G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. Furthermore, it displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. Oral administration of G-749 yielded complete tumor regression and increased life span in animal models. Thus, G-749 appears to be a promising next-generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/FLT3-TKD mutants and further shows the ability to overcome drug resistance.
- Published
- 2014