Hatcher, John M. Weisberg, Ellen Sim, Taebo Stone, Richard M. Liu, Suiyang Griffin, James D. Gray, Nathanael S. 2024-01-20T04:30:48Z 2024-01-20T04:30:48Z 2021-09-04 2016-05 1948-5875 https://pubs.kist.re.kr/handle/201004/124128 For a subpopulation of acute myeloid leukemia (AML) patients, the mutationally activated tyrosine kinase FLT3, has emerged as a promising target for therapy. The development of drug resistance due to mutation is a growing concern for mutant FLT3 inhibitors, such as PKC412, Quizartinib, PLX3397, and Crenolanib. Thus, there is a need to develop novel FLT3 inhibitors that overcome these mutations. Here we report the development of a novel type I ATP competitive inhibitor, JH-IX-179, that is extremely potent and selective for FLT3. JH-IX-179 also has the highest affinity for three constitutively active isoforms of FLT3 (FLT3-ITD, FLT3-N841I, and FLT3-D835V) compared to a panel 456 other kinases. The unique and specific kinase inhibition profile suggests that this chemotype may represent an attractive starting point for the development of further improved FLT3 inhibitors with therapeutic potential in tumors harboring deregulated FLT3 activity. English AMER CHEMICAL SOC ACUTE MYELOID-LEUKEMIA INTERNAL TANDEM DUPLICATION TYROSINE KINASE INHIBITOR ACTIVATING MUTATION FLT3 INHIBITORS SORAFENIB THERAPY SU11248 GENE D835 Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor Article 10.1021/acsmedchemlett.5b00498 1 ACS MEDICINAL CHEMISTRY LETTERS, v.7, no.5, pp.476 - 481 ACS MEDICINAL CHEMISTRY LETTERS 7 5 476 481 scie scopus 000375969400009 2-s2.0-84969533903 Chemistry, Medicinal Pharmacology & Pharmacy Article ACUTE MYELOID-LEUKEMIA INTERNAL TANDEM DUPLICATION TYROSINE KINASE INHIBITOR ACTIVATING MUTATION FLT3 INHIBITORS SORAFENIB THERAPY SU11248 GENE D835 Acute myeloid leukemia FLT3 JH-IX-179 kinase inhibition profile chemotype