FLT3 D835V

While there are numerous examples of KIT TKIs that do not inhibit FLT3 (imatinib, avapritinib, dasatinib), to date, all clinically active FLT3 TKIs (quizartinib, gilteritinib, midostaurin, sorafenib) fail to spare KIT inhibition...Compared to FF-10101 and gilteritinib, BGS-2456 exhibited the least amount of hematologic toxicity, facilitating in vitro proliferation and differentiation of normal hematopoietic progenitor cells even at 100x EC50 concentration against Molm14 cells... This is the first description of a potent and exquisitely specific FLT3 inhibitor that spares KIT inhibition and displays no myelosuppression in vitro at >100x EC50 concentration. The potent inhibitory effects of BGS-2456 on both D835Y and F691L mutants support its promise as a best-in-class TKI for the treatment of FLT3-mutant AML. Efforts to molecularly dissect the basis of the high degree of selectivity of BGS-2456 are ongoing.

Herein, we describe the discovery of compound LT-540-717 (32), a potent FLT3 inhibitor (IC: 0.62 nM), starting from FN-1501...Furthermore, 32 showed an acceptable bioavailability (F = 33.3% in rat and 72.7% in beagles), a suitable half-life time (T = 3.5 h in rat and T = 11.1 h in beagles), and a satisfactory metabolic stability. In summary, these results show the therapeutic potential of 32 to become a new anti-AML drug, especially for AML harboring dual FLT3 (ITD, TKD) mutations.

Moreover, the treatment with compound 13 led to robust inhibition of FLT3 autophosphorylation on Tyr589/591 in MV4-11 cells. In summary, our data demonstrated that 13 was worthy of further study for the treatment of AML.

The present pioneer study provides a basis for advanced optimization of drug potency, selectivity, specificity, and other properties desired of anticancer drug leads. Studies are ongoing to determine the full therapeutic properties of Lwk-n019 and the detailed mechanisms of FLT3 in TOP inhibition.

Several FLT3 inhibitors have been developed such as the first generation multikinase inhibitor Midostaurin which is approved for newly diagnosed FLT3 mutant AML in combination with induction chemotherapy...Herein we describe 2082-0047, a novel tyrosine kinase inhibitor with sub-nanomolar potency against FLT3 mutant AML, including TKD mutations...Our non-GLP in vivo safety studies confirmed a broad therapeutic window of 2082-0047. Ongoing Investigational New Drug (IND) enabling studies will include comparing the effect of 2082-0047 to gilteritinib in an immunocompetent syngeneic AML murine model harboring both a Flt3-ITD and F691 TKD gatekeeper mutation.

Clinical molecular testing in our cohort revealed these gene alterations mainly in pediatric patients and enabled diagnosis, prognosis, and risk stratification allowing the use of clinically actionable therapeutic targets in some cases. It also contributed toward a useful data set for further analysis and potential for novel drug development. Longer-term followup incorporating therapy and outcomes information would be valuable.

HM43239 inhibited FcγR-induced SYK and JAK/STAT5 activation in KG-1a (FLT3-WT) cells that upregulate RAS signaling which is a mechanism of acquired resistance to gilteritinib. Its ability to also inhibit SYK and, by reducing the activity of these upstream kinases, to also impair the activity of EKR1/2 and JAK/STAT5 that participate in rescue pathways, makes this a particularly interesting molecule with the potential of offsetting the development of resistance that is common with other FLT3 inhibitors. A Phase 1/2 trial of HM43239 in patients with AML is open and accruing patients (NCT03850574).

The protein-inhibitor interactions displayed that the motions of PHE-830 influenced that of sorafenib, but not to crenolanib. These findings indicated that the structural impact brought by D835V mutation should be considered in designing novel drugs to overcome resistance to FLT3-D835V.

No clear myelosuppression was observed in the treated group of 36 in the MPO strain of zebrafish, even at 10 μM. In summary, our data demonstrated that 36 may represent a promising candidate for the treatment of FLT3 mutant AML.

Clinical molecular testing in our patients revealed gene alterations that provide refinement of diagnosis, prognosis, and risk stratification allowing the use of clinically actionable therapeutic targets in some cases. It also contributes toward a useful data set for further analysis and impactful targeted management. Longer-term follow-up incorporating therapy and outcomes information would be valuable.

Trial Design: This is an ongoing, open-label, multicenter, first in human phase I/II trial enrolling adult FLT3 mutated and FLT3 wild-type patients with AML who have relapsed or refractory disease after at least one prior line of therapy, what can include prior FLT3 inhibitors such as gilteritinib, midostaurin. This study is currently recruiting patients at multiple sites in the Republic of Korea and the USA. Clinical trial information: NCT03850574.