BMN 673

BMN 673 is a novel and highly potent poly (ADP-ribose) polymerase1 and 2 (PARP1/2) inhibitor with K_i = 1.2 nM and K_i = 0.87nM, respectively^[1]. BMN 673 interferes the DNA single-strand breaks repair function of PARP1/2 and emerges as an anticancer agents^[2].

In vitro, BMN 673 (1nM-10μM) treatment on wild-type avian B-lymphoblast DT40 cells for 72h produced PARP-mediated cytotoxicity with IC₉₀ value of 30nM but shows no cytotoxic effect on PARP1^−/− DT40^[3]. BMN 673 (0.01, 0.05, 0.1, 0.5, 1, 5, and 10nM) incubated wild‐type triple negative breast cancer MDA‐MB‐231 cells for 6 to 12 days and exerted inhibitory effects on cells by inducing apoptosis, multicaspase activity, G2/M arrest, and altering the expression levels of apoptosis‐related genes^[4].

In vivo, BMN 673 (1mg/kg) was administered via i.p. injection every other day for a total of five doses into Brca^−/− murine ovarian carcinoma cells engrafted FVB mice. BMN 673 significantly increased the number of peritoneal CD8⁺ T cells and NK cells as well as their production of IFN-γ and TNF-α, and finally increased mice survival rate^[5]. Oral administration of BMN 673 for 28 days (0.1mg/kg/day or 0.33mg/kg/day) into nude mice bearing subcutaneous human embryonic lung fibroblast cells tumor significantly inhibited tumor progression with no animal lethality or significant weight loss^[6]. BMN 673 (0.33mg/kg) was administered by oral gavage once daily into pancreatic ductal adenocarcinoma (PDAC) xenografted mice models for four weeks. BMN 673 resulted in significant tumor growth inhibition and reduced induced apoptosis by increasing cleaved caspase-3^[7].

References:
[1] Wang B, Chu D, Feng Y, et al. 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. J Med Chem. 2016 Jan 14;59(1):335-57.
[2] De Bono JS, Mina LA, Gonzalez M, et al. First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. J Clin Oncol. 2013; 31(suppl):abstr 2580.
[3] Murai J, Huang S N, Renaud A, et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2014 Feb;13(2):433-43.
[4] Eskiler G G, Cecener G, Egeli U, Tunca B. BMN 673 (talazoparib): A potent PARP inhibitor for triple negative breast cancer with different genetic profile. J Biochem Mol Toxicol. 2019 May;33(5):e22286.
[5] Huang H, Wang L, Cong Z Y, et al. The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1(-/-) murine model of ovarian cancer. Biochem Biophys Res Commun. 2015 Aug 7;463(4):551-6.
[6] Shen Y Q, Rehman F L, Feng Y, et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency.Clin Cancer Res. 2013 Sep 15;19(18):5003-15.
[7] Andrei A Z, Hall A, Smith A L, et al. Increased in vitro and in vivo sensitivity of BRCA2-associated pancreatic cancer to the poly(ADP-ribose) polymerase-1/2 inhibitor BMN 673. Cancer Lett. 2015 Aug 1;364(1):8-16.

BMN 673是一种新型且高效的聚ADP核糖聚合酶1和2（PARP1/2）抑制剂，对PARP1的K_i为1.2nM，对PARP2的K_i为0.87nM^[1]。BMN 673干扰PARP1/2的DNA单链断裂修复功能，可被作为一种抗癌药物^[2]。

在体外实验中，BMN 673（1nM-10μM）处理野生型鸟类B淋巴母细胞DT40细胞72小时，产生PARP介导的细胞毒性，IC₉₀值为30nM，但对PARP1^−/−的DT40细胞没有细胞毒性^[3]。 BMN 673（0.01、0.05、0.1、0.5、1、5和10nM）与野生型三阴性乳腺癌MDA-MB-231细胞共孵育6–12天，通过诱导凋亡、多caspase活性、G2/M阻滞及改变凋亡相关基因表达水平发挥细胞抑制作用^[4]。

在体内实验中，BMN 673（1mg/kg）每两天腹腔注射一次，共五次，在Brca^−/−小鼠卵巢癌组织移植FVB小鼠中显著增加腹腔CD8⁺ T细胞和NK细胞数量及其IFN-γ和TNF-α产生，最终提高小鼠生存率^[5]。BMN 673经口服28天（0.1mg/kg/day或0.33mg/kg/day）给予携带皮下人胚胎肺成纤维细胞肿瘤的裸鼠，BMN 673显著抑制肿瘤进展且没有造成动物死亡或显著体重下降^[6]。BMN 673（0.33mg/kg）每日一次经口灌胃给药于胰腺导管腺癌（PDAC）异种移植小鼠模型，BMN 673显著抑制肿瘤生长并通过增加cleaved caspase-3诱导凋亡^[7]。