Discovery and Characterization of (8<i>S</i>,9<i>R</i>)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1<i>H</i>-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3<i>H</i>-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent

TLDR

We discovered and developed a novel series of tetrahydropyridophthlazinones as PARP1/2 inhibitors. The stereospecific dual chiral‑center‑embedded structure of the lead compound enables extensive and unique binding interactions with PARP1/2 proteins. The lead compound (8S,9R)-47 (talazoparib) shows nanomolar potency against PARP1/2, inhibits PARylation and cancer cell proliferation, is orally bioavailable, and has demonstrated antitumor efficacy in BRCA1 mutant xenografts while completing phase 1 trials and progressing to phase 2/3 studies.

Abstract

We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC50 of 2.51 nM and prevents proliferation of cancer cells carrying mutant BRCA1/2, with EC50 = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8S,9R)-47 has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline BRCA1/2 deleterious mutations.