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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41CA250761-01A1
Agency Tracking Number: R41CA250761
Amount: $298,928.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 102
Solicitation Number: PA19-270
Solicitation Year: 2019
Award Year: 2020
Award Start Date (Proposal Award Date): 2020-09-18
Award End Date (Contract End Date): 2021-08-31
Small Business Information
Sunnyvale, CA 94089-1202
United States
DUNS: 112566918
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (650) 485-3626
Business Contact
Phone: (650) 283-9100
Research Institution
SAN FRANCISCO, CA 94143-0962
United States

 Nonprofit College or University

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 andamp; 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 in order to generate a target product profile for the use of the
novel covalent FLT3 inhibitor in treating AML.PROJECT NARRATIVE
Acute myeloid leukemia (AML) is one of the most common cancers in adults and has a low long-term survival
rate. Chemotherapy is the standard-of-care for AML; however, due to disease heterogeneity, patients often
experience treatment failure. Targeted therapies employing tyrosine kinase inhibitors have shown promise, but
they are associated with drug-resistance and side effects. Improved targeted approaches for AML are
desperately needed to improve patient outcomes. BridGene Biosciences is developing a covalent small-molecule
kinase inhibitor that acts via a novel mode of action to provide a more potent, selective, and safe treatment for
AML patients.

* Information listed above is at the time of submission. *

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