Abstract 2631: Discovery of SC110237, a highly potent, selective and orally active FLT3 inhibitor for the treatment of acute myeloid leukemia
Authors: Kong Norman , Gao Daxin , Yang Heping , Yu Yajun 
Published: August 2015

Abstract
FLT3 (Fms-like tyrosine kinase 3) is the most frequently mutated gene in acute myeloid leukemia (AML). Activating Flt3 mutations occur in about 30% of patients with AML, often as internal tandem duplication(ITD) mutations. These mutations are associated with the poor prognosis. Here, we report the Denovo preclinical candidate SC110237, a novel, selective, highly potent, and orally active FLT3 inhibitor which has very similar antitumor efficacy in MV4-11 xenograft models, but has better cardiac safety, and more favorable pharmacokinetic profiles compared with AC220, the first-in-class FLT3 inhibitor in clinical trial.
SC110237 showed potent activity against FLT3 enzyme (IC50 = 91 nM) and anti-proliferative activity against MV4-11 tumor cells (SC110237 IC50 = 0.09 nM, AC220 IC50 = 0.56 nM). Unlike most FLT3 inhibitors in clinical trials, SC110237 showed good selectivity within the Class III RTK family. In vivo, SC110237showed excellent efficacy in the subcutaneous models of AML and CEL (Chronic Eosinophilic Leukemia): MV4-11, MOLM-13 and EOL-1 model. MV4-11, MOLM-13 human AML cells have FLT3-ITD mutations, EOL-1 human CEL (Chronic Eosinophilic Leukemia) cells have FIP1L1-PDGFRA and over-expression of wild-type FLT3 receptor. In s.c. MV4-11 AML model, SC110237-2 (2, 6, 18 mg/kg) demonstrated potent activity. Tumor is completely eradicated in all groups even at the lowest dose of 2 mg/kg, with prolonged inhibition effect on tumor growth after drug withdrawal. At the lowest dose of 2 mg/kg for SC110237-2, there is 1 tumor re-growth until day 55 (12 days post last dose) compared to 3 tumors re-growth (one of the mice died) on the day 55 (12 days post dose) for AC220 at the same dose of 2 mg/kg. At higher dose of 6 mg/kg for SC110237-2, there is no sign of tumor re-growth until day 82 (39 days post last dose) comparing with 1 tumor re-growth on the day 76 (33 days post dose) for AC220 at the same dose of 6 mg/kg. In s.c. MOLM-13 and EOL-1 models, Tumor is completely eradicated in 4/8 mg/kg groups after 5 or 8 days dosing. SC110237-2 has no inhibition on CYP450 2C9, 2D6, 3A4 (Midazolam). Exposure of SC110237 is similar to that of AC220 which has the best PK profile among FLT3 inhibitors, while Cmax of SC110237 is lower than that of AC220. SC110237-2 exhibits linear dose-proportional exposure in mice and dog, and easier to adjust the dosage. Bioavailability of SC110237-2 in dog is 35%. To evaluate the effects of SC110237-2 and AC220 on the cardiovascular system, real time ECG was observed in conscious monkeys by a telemetry system. No abnormal phenomena have been observed in the 20 and 40 mg/kg SC110237 group, only with faster heart rate in the 80 mg/kg SC110237-2. On the other hand, 40 mg/kg AC220 can obviously prolong the QTcB interval. In conclusion, SC110237 exhibited a remarkable anti-tumor activity with favorable pharmacokinetic profiles and showed promise as a novel oral drug for the treatment of acute myeloid leukemia.
Citation Format: Norman Kong, Daxin Gao, Heping Yang, Yajun Yu. Discovery of SC110237, a highly potent, selective and orally active FLT3 inhibitor for the treatment of acute myeloid leukemia. [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 2631. doi:10.1158/1538-7445.AM2015-2631