Abstract B230: NMS-P948, a potent dual FLT3/KIT inhibitor, also active on secondary resistance mutations.

FMS-like tyrosine kinase 3 (FLT3) 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 deletion 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-P948 is an alkoxy-indazole derivative potent dual inhibitor of FLT3 and KIT (IC 50 26 and 89 nM, respectively), active also against FLT3 and KIT mutations that confer secondary resistance, such as the gatekeeper mutation T670I of KIT. It is a very selective compound, resulting, when tested on a panel of more than 150 human tumor cell lines, strongly active only on cell lines whose proliferation is driven by one of these two kinases (for FLT3: Eol-1, IC 50 = 8 nM; MV-4–11, IC 50 = 8 nM; MOLM-13, IC 50 = 18 nM and for KIT: GIST-430 IC 50 = 7 nM and GIST-882 IC 50 = 99 nM). Mechanism of action is demonstrated on both kinases, with activating and resistance mutations, at low nanomolar concentrations. NMS-P948 has good oral bioavailability in rodents. Antitumor efficacy is observed at as low as 10 mg/kg in xenograft models and no toxicity in terms of body weight loss was observed up to 60 mg/kg. In disseminated human AML MOLM-13 model (FLT3-ITD) NMS-P948 produces a very prolonged survival of treated mice (T/C= 390 at 60 mg/kg OS daily × 10) and this antitumor efficacy results superior to that of quizartinib administered with the same schedule at the MTD (T/C= 207 at 40 mg/kg). In conclusion, NMS-P948 is a promising dual inhibitor of mutated FLT3 and KIT with good in vitro and in vivo pharmacological and pharmacokinetic characteristics and with the potential to act also on patients that developed resistance to first line therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B230.