# Novel drug to treat poor prognosis AML

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $234,662

## Abstract

PROJECT SUMMARY/ABSTRACT
The incidence of acute myeloid leukemia (AML) has been on the rise. Activating mutations in the fms like tyrosine
kinase 3 (FLT3) are present in 25-30% of AML, ~10% of myelodysplastic (MDS) and 5-6% of acute lymphoblastic
leukemia (ALL) patients. The common mutations include missense point mutations in the kinase domain, in
frame deletions and internal tandem duplications (ITD) in the juxta membrane domain leading to constitutive
activation of the receptor tyrosine kinase (RTK) activity. FLT3-ITD is present in ~25% AML patients with normal
karyotype and is considered an independent prognostic marker. Patients with FLT3-ITD mutation are at a higher
risk of disease relapse and reduced overall 5-year survival. Activating mutations of FLT3 contribute to
deregulated proliferation of hematopoietic progenitor cells leading to myeloproliferative neoplasm (MPN). We
and others have shown that co-occurrence of mutations that enhance the self-renewal of hematopoietic stem
cells (HSC) can transform these cells into AML.However, despite the high prevalence rate and the clinical
significance of FLT3 mutations in the pathogenesis of AML, there are limited options for targeted therapy. In
2017, Midostaurin (Rydapt), a multi-kinase inhibitor became the first targeted therapy to be approved by food
and drug administration (FDA) for the treatment of AML, followed by Gilteritinib (Xospata), a FLT3 and AXL1
specific inhibitor in 2018. Additional experimental drugs specific for mutant FLT3 in various stages of clinical
trials including Quizartinib and Crenolanib have also been described, although they are known to develop both
intrinsic and acquired resistance in response to FLT3 targeted therapy the intrinsic resistance in AML to therapy
with FLT3 directed inhibitors depends on the presence of co-occurring mutations acquired resistance is due to
activation of parallel survival pathways and/or acquisition of secondary mutations in FLT3-ITD. More recently,
emergence of RAS mutations has been reported in AML patients treated with Gilteritinib. Thus, there is a critical
unmet need to identify and develop potent and selective inhibitor(s) for mutant FLT3 to provide additional
therapeutic options for treating AML patients with these mutations. To this end, we have recently identified a
novel class of naphthyridine based FLT3 inhibitors that not only selectively target FLT3-ITD at sub-nanomolar
concentrations but are also effective against the drug resistance conferring secondary mutations acquired in
response to targeted therapy. Based on our preliminary data, we hypothesize that in comparison to recently FDA
approved FLT3 inhibitors, including Gilteritinib, we have identified novel and potent drugs with inhibitory activity
against FLT3-ITD as well as gatekeeper mutations of FLT3 for a more robust and durable AML treatment. We
will utilize two of these inhibitors (KRX-101 & KRX-107; also defined as HSN608 & HSN748, respectively) to
further character...

## Key facts

- **NIH application ID:** 10290199
- **Project number:** 1R21CA263239-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Reuben Kapur
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $234,662
- **Award type:** 1
- **Project period:** 2021-07-02 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10290199

## Citation

> US National Institutes of Health, RePORTER application 10290199, Novel drug to treat poor prognosis AML (1R21CA263239-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10290199. Licensed CC0.

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