Abstract 3754: Characterization of NMS-P285, a new highly selective and potent BRAF inhibitor

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Aberrant activation of the MAPK-mediated pathway components, RAF-MEK-ERK, is frequently found in human cancers and clearly contributes to oncogenesis. In particular, one of the three isoforms of RAF, BRAF, presents activating somatic mutations in 60% of melanomas, 50% of thyroid cancers, 10% of colon and 20% ovarian carcinomas. The most common BRAF mutation, substitution of glutamic acid for valine at position 600 within the activation segment of the kinase domain, accounts for 90% of mutated BRAF cases, and results in elevated kinase activity with consequent enhanced promotion of cell survival and proliferation. BRAF selective inhibitors as vemurafenib and dabrafenib have recently shown excellent results in patients with advanced melanoma expressing BRAF V600E mutant form. Here we describe the in vitro and in vivo properties of a novel potent and selective BRAF inhibitor belonging to the arylthiazole class of compounds. This, NMS-P285, is a potent inhibitor of both wild-type and mutated BRAF, with no cross-reactivity in a panel of 61 kinases. This compound occupies the ATP-binding pocket of the activated form of the enzyme (DFG motif in), partly filling the kinase back pocket, (i.e. type I ½ inhibitors). NMS-P285 has an antiproliferative activity in the low nanomolar range only against cell lines bearing BRAF V600E or V600D mutations. Its mechanism of action is confirmed: a strong inhibition of MAPK pathway was observed in BRAF mutated cells whereas in non-BRAF mutated cells MEK activation was not observed. NMS-P285 possesses a favourable in vitro ADME profile and a very good preliminary PK in mouse. When orally administered to mice with BRAF mutated human xenograft tumors, NMS-P285 resulted more potent than both vemurafenib and dabrafenib demonstrating high antitumor activity with strong and persistent tumor regression observed in all mice. Mechanism of action was demonstrated also ex vivo in A375 bearing mice: MAPK pathway resulted to be completely inhibited up to 6 hours after a single treatment at 30 mg/kg. In conclusion, NMS-P285 is a candidate suitable for preclinical development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3754. doi:1538-7445.AM2012-3754