title: Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Avenue, Longwood Center LC-2209, Boston, Massachusetts 02115, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Hatcher
authors.affiliation: Department of Medical Oncology and Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 136-791, Korea; Graduate School of Converging Science and Technology, KU-KIST, 145, Anam-ro, Seongbuk-gu, Seoul 136-713, Korea.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.affiliation: Department of Medical Oncology and Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Department of Medical Oncology and Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Suiyang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology and Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Avenue, Longwood Center LC-2209, Boston, Massachusetts 02115, United States.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
keywords: Acute myeloid leukemia; FLT3; JH-IX-179; chemotype; kinase inhibition profile