Johannes Jeffrey W, Almeida Lynsie, Barlaam Bernard, Boriack-Sjodin P Ann, Casella Robert, Croft Rosemary A, Dishington Allan P, Gingipalli Lakshmaiah, Gu Chungang, Hawkins Janet L, Holmes Jane L, Howard Tina, Huang Jian, Ioannidis Stephanos, Kazmirski Steven, Lamb Michelle L, McGuire Thomas M, Moore Jane E, Ogg Derek, Patel Anil, Pike Kurt G, Pontz Timothy, Robb Graeme R, Su Nancy, Wang Haiyun, Wu Xiaoyun, Zhang Hai-Jun, Zhang Yue, Zheng Xiaolan, Wang Tao
AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
AstraZeneca R&D Alderley Park , Macclesfield, Cheshire SK10 4TG, United Kingdom.
ACS Med Chem Lett. 2015 Jan 13;6(3):254-9. doi: 10.1021/ml5003663. eCollection 2015 Mar 12.
The canonical Wnt pathway plays an important role in embryonic development, adult tissue homeostasis, and cancer. Germline mutations of several Wnt pathway components, such as Axin, APC, and ß-catenin, can lead to oncogenesis. Inhibition of the poly(ADP-ribose) polymerase (PARP) catalytic domain of the tankyrases (TNKS1 and TNKS2) is known to inhibit the Wnt pathway via increased stabilization of Axin. In order to explore the consequences of tankyrase and Wnt pathway inhibition in preclinical models of cancer and its impact on normal tissue, we sought a small molecule inhibitor of TNKS1/2 with suitable physicochemical properties and pharmacokinetics for hypothesis testing in vivo. Starting from a 2-phenyl quinazolinone hit (compound 1), we discovered the pyrrolopyrimidinone compound 25 (AZ6102), which is a potent TNKS1/2 inhibitor that has 100-fold selectivity against other PARP family enzymes and shows 5 nM Wnt pathway inhibition in DLD-1 cells. Moreover, compound 25 can be formulated well in a clinically relevant intravenous solution at 20 mg/mL, has demonstrated good pharmacokinetics in preclinical species, and shows low Caco2 efflux to avoid possible tumor resistance mechanisms.
经典Wnt信号通路在胚胎发育、成体组织稳态及癌症中发挥重要作用。几种Wnt信号通路成分（如Axin、APC和β-连环蛋白）的种系突变可导致肿瘤发生。已知抑制端锚聚合酶（TNKS1和TNKS2）的聚（ADP-核糖）聚合酶（PARP）催化结构域可通过增强Axin的稳定性来抑制Wnt信号通路。为了在癌症临床前模型中探究抑制端锚聚合酶和Wnt信号通路的后果及其对正常组织的影响，我们寻找了一种具有合适理化性质和药代动力学的TNKS1/2小分子抑制剂，用于体内假说验证。从一个2-苯基喹唑啉酮活性化合物（化合物1）开始，我们发现了吡咯并嘧啶酮化合物25（AZ6102），它是一种有效的TNKS1/2抑制剂，对其他PARP家族酶具有100倍的选择性，并且在DLD-1细胞中显示出5 nM的Wnt信号通路抑制作用。此外，化合物25可以很好地配制成20 mg/mL的临床相关静脉注射液，在临床前物种中已证明具有良好的药代动力学，并且显示出低Caco2外排率，以避免可能的肿瘤耐药机制。
