Related Experiment Video
Updated: Mar 21, 2026
Comet Assay to Quantify DNA Damage in FLT3 Mutant-expressing 32D Cells after Exposure to Type I and Type II FLT3 Inhibitors
Published on: October 17, 2025
Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor
John M Hatcher1, Ellen Weisberg2, Taebo Sim3
1Department 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.
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.
Insights
Researchers developed JH-IX-179, a potent FLT3 inhibitor for acute myeloid leukemia (AML). This novel compound overcomes resistance mutations, offering new therapeutic potential for FLT3-driven cancers.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML).
- Existing FLT3 inhibitors face challenges due to acquired drug resistance.
- Novel inhibitors are needed to overcome resistance mechanisms in FLT3-mutated AML.
Purpose of the Study:
- To develop a novel FLT3 inhibitor effective against resistant mutations.
- To characterize the potency and selectivity of the new inhibitor, JH-IX-179.
- To explore the therapeutic potential of JH-IX-179 in FLT3-deregulated tumors.
Main Methods:
- Design and synthesis of a novel type I ATP-competitive inhibitor, JH-IX-179.
- Biochemical assays to determine FLT3 inhibitory potency and selectivity against a panel of 456 kinases.
- Evaluation of affinity for constitutively active FLT3 isoforms (FLT3-ITD, FLT3-N841I, FLT3-D835V).
Main Results:
- JH-IX-179 demonstrates high potency and selectivity for FLT3.
- The inhibitor exhibits the highest affinity for key active FLT3 isoforms.
- JH-IX-179 shows a unique kinase inhibition profile, distinct from other FLT3 inhibitors.
Conclusions:
- JH-IX-179 is a potent and selective FLT3 inhibitor with potential to overcome resistance.
- Its unique profile makes it a promising starting point for developing next-generation FLT3 inhibitors.
- This compound holds therapeutic promise for AML and other FLT3-driven malignancies.
More Related Videos
08:49Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
10:33Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
Published on: October 26, 2015