432 ODM-203, a novel, selective and balanced FGFR and VEGFR inhibitor with strong anti-tumor activity in FGFR- and VEGFR-dependent cancer models

Abstract

thought to play an important role in carcinogenesis by protecting cells from apoptosis. Recent publications disclosing FASN inhibitors suggest a pharmacophore common to many chemical series, wherein an aromatic group and an acylated cyclic amine are attached to a central scaffold. We postulated that imidazolinone would be an acceptable and drug-like scaffold, inspired by the precedent of irbesartan, an approved antihypertensive drug with a spirocyclopentyl-imidazolinone core. This hypothesis led to the discovery of a new series of imidazolinone-based FASN inhibitors. Extensive structure–activity relationship work in our laboratories resulted in numerous molecules with potent enzyme and cell activity, selectivity, and oral bioavailability. One such compound is a potent inhibitor of human FASN enzymatic activity (IC50 = 28 nM) and also potently inhibits proliferation of A2780 ovarian cells in lipid-reduced medium (IC50 = 13 nM). Addition of palmitate to the medium rescues the cells from FASN inhibition, demonstrating on-target effects. Potent activity is also seen in other cancer cells such as PC3M (IC50 = 25 nM) and LnCaP-Vancouver prostate cells (IC50 = 66 nM). This lead compound is highly bioavailable (F 61%) in mice and shows good plasma and tumor exposures after oral dosing. In a pharmacodynamics (PD) model in H460 lung xenograft-bearing mice, oral treatment resulted in elevated tumor levels of malonyl-CoA and decreased tumor levels of palmitate. This compound and other members of the imidazolinone series potently inhibit the FASN KR domain (IC50 = 54 nM); specific binding to KR was confirmed by co-crystal structures of several examples. In summary, we discovered a new series of FASN inhibitors built upon an imidazolinone scaffold that are potent in enzyme and in cell proliferation assays, are highly bioavailable, and bind to KR domain. Moreover, rescue of lipid-reduced cellular activity upon addition of palmitate suggests selectivity, and PD studies in tumor-bearing mice confirm target engagement.