Pre-IND study of PMT-254, a pan-FLT3 inhibitor for the treatment of FLT3 driven cancers.

DESCRIPTION provided by applicant Pathological activating mutations in the FLT kinase represent the most common genetic alteration in patients with acute myeloid leukemia AML occurring in approximately one third of cases Recently we performed translational studies that identified drug resistant kinase domain mutations in FLT ITD at the time of relapse in AML patients treated with the FLT inhibitor quizartinib AC validating FLT ITD as a therapeutic target in human AML N Shah et al Nature To facilitate the rapid identification of potential therapeutic agents that can treat AML more effectively a cancer with no newly approved efficacious treatments we have created a novel fragment approach to discover kinase inhibitors and established a series of in vitro and in vivo assays to streamline the development of FLT inhibitors for AML As a result a highly potent FLT inhibitor clinical candidate PMT was identified PMT is the most potent selective FLT inhibitor developed to date displaying an IC of nM for FLT ITD transformed Ba F cells Further PMT achieves low nanomolar inhibition of quizartinib resistant F L D V and D Y mutants Notably all clinically active investigational FLT inhibitors are much less potent and do not achieve a similar mutant activity profile In human AML cell lines PMT achieves an IC of nM in both MV and Molm AML lines In Molm cells harboring an endogenous F L or D Y mutation PMT achieves a nM or nM IC value respectively PMT does not impair the growth of parental Ba F cells even at a concentration of nM Screened against a kinase panel of kinases PMT was found exclusively selective for FLT and FLT mutants Clearly PMT is unlike any FLT inhibitor as manifested by its ultra potency and ultra selectivity and therefore has extraordinary potential to transform treatment outcomes for patients with FLT ITD driven AML In MV xenograft studies PMT dosed PO mg kg shrunk tumors to undetectable levels in as little as four days p andlt Control tumors that reached a tumor volume of mm were dosed at PO and mg kg which reduced tumor burden to undetectable levels in days Undetectable tumors from original treatment were allowed to rebound to a volume of mm at which point treatment with PMT commenced PO mg kg which again caused reduction in tumor volume to undetectable levels Every mouse treated with PMT was essentially cured of tumor burden and displayed no signs of toxicity even after receiving daily oral doses for over consecutive days In this proposal we wish to further develop our FLT inhibitor by completing pilot formulation PK PD and toxicity studies This will acquire pivotal data necessary to justify completing an investigative new drug IND package We have completed a preliminary andapos proof of conceptandapos data package but specific facets to preclinical development are lacking that warrant additional pre IND development With the completion of this proposal we will have a data package that will merit full IND development PUBLIC HEALTH RELEVANCE A pan FLT tyrosine kinase inhibitor has been identified that can potentially offer AML cancer patients a more effective treatment The inhibitor is considerably more safe and effective over previous clinical compounds in the same class The completion of the proposed research will help this breakthrough medicine reach patients quickly and safely