Discovery and Characterization of (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 (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent

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.

Increased PARP1‐DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1‐DNA trapping is correlated with PARP1 inhibitor's cytotoxicity

“…The DSB and SSB data were from the 60-min time point in (d) and Supporting Information Figure S4d and S6d. 5,6,13,38,43,44 Because the autoP-ARylation of PARP1 on DNA directly contributes to its dissociation from DNA, 37 the FA models can reflect the inhibition degree of the polymerase activity of the PARP1 protein that binds to DNA by PARPis. capability of PARPis in inhibiting the dissociation of PARP1 from DNA in cell-free DSB (r = 0.9984; p < 0.0001) and SSB (r = 0.9849; p = 0.0022) FA models and their cytotoxicity in 17 HR-deficient cell lines.…”

Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent

“…D). There is a growing literature indicating that the protein SFLN11 is involved in the response of cells to DNA damaging agents such as etoposide and carboplatin and with the PARP inhibitors . SLFN11 gene and exons expression correlated with sensitivity to etoposide/carboplatin, to talazoparib and to talazoparib with etoposide/carboplatin; however, both the talazoparib/etoposide/carboplatin responsive and nonresponsive SCLC lines expressed SLFN11.…”

Fluorine‐Containing Drugs Approved by the FDA in 2018

“…Firstly, it was found that (8 S ,9 R )‐enantiomer was active, whereas (8 R ,9 S )‐enantiomer was inactive. Secondly, the substituted groups, including 5‐fluoro, 8‐(4‐fluorophenyl), and 9‐(1‐methyl‐1,2,4‐triazol‐5‐yl) played a crucial role in the cellular PARylation activity, metabolic stability and cytotoxicity …”

“…Secondly, the substituted groups, including 5-fluoro, 8-(4-fluorophenyl),a nd 9-(1-methyl-1,2,4-triazol-5-yl) played a crucial role in the cellularP ARylation activity,metabolic stability and cytotoxicity. [43] The same year,X ua nd co-authors developed as ynthetic route for the preparation of talazoparib in 30 gs cale by chiral resolution (Scheme22). [44] Methyl3 -amino-5-fluorobenzoate (124)a nd 3-(4-fluorophenyl)-3-oxopropanoic acid (125)w ere selected as the startingm aterials.…”