Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor

John M. Hatcher, Ellen Weisberg, Taebo Sim, Richard M. Stone, Suiyang Liu, James D. Griffin, Nathanael S. Gray

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)476-481
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume7
Issue number5
DOIs
Publication statusPublished - 2016 May 12

Fingerprint

4'-N-benzoylstaurosporine
Phosphotransferases
Mutation
Drug Resistance
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Tumors
Protein Isoforms
Adenosine Triphosphate
Therapeutics
Pharmaceutical Preparations
Neoplasms
5-((5-chloro-1H-pyrrolo(2,3-b)pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine
quizartinib
crenolanib

Keywords

  • Acute myeloid leukemia
  • chemotype
  • FLT3
  • JH-IX-179
  • kinase inhibition profile

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

Hatcher, J. M., Weisberg, E., Sim, T., Stone, R. M., Liu, S., Griffin, J. D., & Gray, N. S. (2016). Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor. ACS Medicinal Chemistry Letters, 7(5), 476-481. https://doi.org/10.1021/acsmedchemlett.5b00498

Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor. / Hatcher, John M.; Weisberg, Ellen; Sim, Taebo; Stone, Richard M.; Liu, Suiyang; Griffin, James D.; Gray, Nathanael S.

In: ACS Medicinal Chemistry Letters, Vol. 7, No. 5, 12.05.2016, p. 476-481.

Research output: Contribution to journalArticle

Hatcher, JM, Weisberg, E, Sim, T, Stone, RM, Liu, S, Griffin, JD & Gray, NS 2016, 'Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor', ACS Medicinal Chemistry Letters, vol. 7, no. 5, pp. 476-481. https://doi.org/10.1021/acsmedchemlett.5b00498
Hatcher, John M. ; Weisberg, Ellen ; Sim, Taebo ; Stone, Richard M. ; Liu, Suiyang ; Griffin, James D. ; Gray, Nathanael S. / Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor. In: ACS Medicinal Chemistry Letters. 2016 ; Vol. 7, No. 5. pp. 476-481.
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