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

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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 in order to generate a target product profile for the use of the novel covalent FLT3 inhibitor in treating AML.