Abstract 798: NMS-P088, a dual FLT3-KIT inhibitor active also on gatekeeper mutations and devoid of QTc prolongation

Abstract

Abstract FLT3 (FMS-like tyrosine kinase 3) and KIT are both members of the class III receptor tyrosine kinase family characterized by an autoinhibitory juxtamembrane (JM) domain that docks with the kinase domain to stabilize a catalytically inactive conformation. Therefore, mutations or deletions in this or in adjacent regions cause constitutive activation of these kinases as observed in 30% of AML patients for FLT3 and in 70% of adult GIST and a subset of melanoma patients for KIT. NMS-P088 is a member of a novel indazole sub-series, which selectively targets both FLT3 and KIT kinases, with different mutations, both primary and secondary, some of which involved in resistance to inhibitors clinically used to target these kinases, such as quizartinib for FLT3 and imatinib for KIT. The compound is able to arrest in vitro growth of human cell lines (AMLs and GISTs) which bear constitutively activated FLT3 or KIT, with IC50s in the low nanomolar range and with high selectivity towards cell lines, including AMLs, which are not dependent on these kinases. When tested against a panel of BA-F3 cells engineered to be driven by different FLT3 or KIT mutants, NMS-P088 compared favorably with reference compounds, both in vitro and in vivo. For example, comparative in vivo tumor inhibition values against BA-F3_FLT3-ITD(F691L) model were 85% for 15 mg/kg NMS-P088 vs. 14% for 40 mg/kg quizartinib. In vivo studies conducted on nude mice bearing the human MOLM-13 AML model revealed that repeated oral administration of NMS-P088 was able to significantly inhibit tumor growth and to increase survival time and that strong inhibition of FLT3 signaling is sustained for at least 48 h after a single treatment. Preclinical profiling of the compound showed a good oral bioavailability in all species, indicated a good therapeutic window in 7-day repeated toxicological studies in rat and in dog and excellent BBB penetration. The low myelotoxicity observed in exploratory toxicological studies suggests that NMS-P088 is potentially well-suited to combination with myelotoxic chemotherapeutic agents and this point is currently subject of preclinical evaluation. Furthermore, no adverse effects on cardiac parameters were observed in a canine telemetry study in which animals were exposed to Cmax levels several fold higher than those required for efficacy in the mouse. NMS-P088 is currently undergoing advanced preclinical development activities. Citation Format: Marina Ciomei, Nadia Amboldi, Sabrina Cribioli, Daniele Casero, Angela Greco, Antonella Isacchi, Enrico A. Pesenti, Daniele Donati, Arturo Galvani, Andrea Lombardi Borgia. NMS-P088, a dual FLT3-KIT inhibitor active also on gatekeeper mutations and devoid of QTc prolongation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 798. doi:10.1158/1538-7445.AM2015-798