# Development of an irreversible covalent inhibitor of FMS-like tyrosine kinase receptor 3 for treating acute myeloid leukemia

> **NIH NIH R41** · BRIDGENE BIOSCIENCES, INC. · 2020 · $298,928

## Abstract

PROJECT SUMMARY
Acute myeloid leukemia (AML), a malignant disease of hematopoietic precursor cells in the bone marrow, is one
of the most common cancers in adults accounting for 1% of all cancers. AML is typically diagnosed later in life
with individuals 60 and older having a long-term survival rate of merely 5-15%. Cytogenic analysis of the
abnormal cells at the time of diagnosis has proven to be an excellent indicator of treatment success as well as
prognosis. Several mutations are associated with AML with the most common ones being in the FMS-like
tyrosine kinase 3 (FLT3) gene leading to the promotion of cytokine independent AML cell survival and
proliferation. There are currently two FDA-approved tyrosine kinase inhibitors (TKIs) for treating patients with
FLT3 mutations; however, studies have shown a significant lack of response to these drugs in upwards of 60%
of patients and a number of side effects due to off-target toxicities. BridGene Biosciences is developing a new
chemical entity to serve as a small-molecule covalent inhibitor of FLT3 in order to address the limitations of FDA-
approved FLT3 inhibitors and those under development. A covalent FLT3 inhibitor has higher potency,
selectivity, and longer residence time than current non-covalent FLT3 inhibitors, and treat drug-resistant
mutations, thus providing a more effective and safe treatment option for AML. BridGene Biosciences’ FLT3
inhibitor, known as BGS2456, has demonstrated selective in vitro growth inhibition activity against AML cell lines
driven by different FLT3 oncogenic mutants. These preliminary efforts provide significant support for the
execution of the proposed Phase I program with the goal of obtaining proof-of-concept for the use of BGS2456
as a best-in-class FLT3 inhibitor for AML. The objective of Aim 1 is to enhance the drug-like properties of
BGS2456 through a medicinal chemistry approach. Synthesized derivatives (Aim 1A) will be ranked according
to pre-determined metrics for potency, selectivity (Aim 1B), and a few other properties to assess their potential
to become drugs (Aim 1C) as determined using standard in vitro assays. The top derivatives will be advanced
to Aim 2, which is focused on characterizing the in vitro potency and selectivity of the derivatives using AML cell
lines (Aims 2A & 2B) and assessing hematotoxicity (Aim 2C). A single lead derivative will be advanced to Aim 3,
which is geared toward obtaining in vivo proof-of-concept for the use of a lead BGS2456 derivative in treating
AML. Initially, PK and tolerability studies (Aim 3A) will be executed to inform dosing then the derivative will be
assessed for in vivo efficacy, which will be defined as enhanced survival and reduction in disease progression
compared to gilteritinib (an FDA-approved FLT3 TKI) in an AML mouse model (Aim 3B). Successful completion
of the proposed Phase I program will support a Phase II project that is focused on completing key
pharmacological and safety assessment studies ...

## Key facts

- **NIH application ID:** 10081364
- **Project number:** 1R41CA250761-01A1
- **Recipient organization:** BRIDGENE BIOSCIENCES, INC.
- **Principal Investigator:** Ping Cao
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $298,928
- **Award type:** 1
- **Project period:** 2020-09-18 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10081364

## Citation

> US National Institutes of Health, RePORTER application 10081364, Development of an irreversible covalent inhibitor of FMS-like tyrosine kinase receptor 3 for treating acute myeloid leukemia (1R41CA250761-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10081364. Licensed CC0.

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