NMS-P088, a CSF-1R, FLT3 and KIT inhibitor with outstanding activity on gatekeeper resistance mutations, high tolerability, and potential for combination therapies

CSF1R, FLT3 and KIT belong to the class III receptor tyrosine kinase family. Mutations or deletions in the autoinhibitory juxtamembrane (JM) domain region present in these kinases cause constitutive activation of FLT3 (30% of AML patients) and KIT (70% of adult GIST and a subset of melanoma and AML patients), while CSF1R is a vital signaling component in Tumor Associated Macrophages (TAMs), controlling tumor infiltration and immunosuppressive functions. NMS-P088 is a novel indazole discovered and being developed by NMS, which potently and selectively targets CSF-1R, FLT3 and KIT, including oncogenic variants with both primary and secondary mutations. NMS-P088 has a highly favorable safety profile in 7-day repeated oral administration studies in rat and non-human primate (therapeutic window >5 compared with exposures required for potent in vivo efficacy). The low myelotoxicity observed in exploratory toxicological studies suggests that NMS-P088 is highly suited to combination with chemotherapeutic agents. Furthermore, the compound possesses excellent BBB penetration and no adverse effects on cardiac parameters were observed in telemetry studies in the dog at Cmax levels exceeding those required for efficacy. In human tumor cell lines in vitro, NMS-P088 potently and selectively arrested growth of FLT3-driven AMLs and KIT-driven GISTs, with IC50s in the low nanomolar range. Against a panel of BA/F3 cells driven by CSF1R or by diverse FLT3 or KIT mutants, including variants implicated in resistance to agents currently in clinic, NMS-P088 compared favorably with reference compounds such as gilteritinib, quizartinib, crenolanib and midostaurin for FLT3. imatinib for KIT and pexidartinib for CSF1R, in terms of both cell proliferation and signaling pathway inhibition. Potent inhibition of CSF1R-dependent signaling was also observed in the human THP1 monocytic and NKM-1 myeloid leukemia cell lines. Efficacy studies in mice bearing human MOLM-13 AML tumors revealed that oral administration of NMS-P088 significantly inhibited tumor growth and increased survival time, while combination with cytarabine was well tolerated and had a greater than additive effect on survival. The outstanding in vitro activity of NMS- P088 on gatekeeper resistance mutations was confirmed in vivo against BA/F3_FLT3-ITD(F691L) tumors, with growth inhibition values of 85% for 15mg/kg NMS-P088 vs. 14% for 40mg/kg quizartinib. Finally, NMS-P088 efficiently and dose-dependently decreased tissue i