SFI CAST Biomedical Innovation Center, Unit for Cell Signaling, Oslo University Hospital, Forskningsparken, Gaustadalleén 21, 0349 Oslo, Norway.
J Med Chem. 2013 Apr 11;56(7):3012-23. doi: 10.1021/jm4000566. Epub 2013 Mar 29.
Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological biotargets with possible applications for the development of novel anticancer therapeutics. A focused structure-activity relationship study was conducted based on the tankyrase inhibitor JW74 (1). Chemical analoging of 1 improved the 1,2,4-triazole based core and led to 4-{5-[(E)-2-{4-(2-chlorophenyl)-5-[5-(methylsulfonyl)pyridin-2-yl]-4H-1,2,4-triazol-3-yl}ethenyl]-1,3,4-oxadiazol-2-yl}benzonitrile (G007-LK), a potent, "rule of 5" compliant and a metabolically stable TNKS1/2 inhibitor. G007-LK (66) displayed high selectivity toward tankyrases 1 and 2 with biochemical IC50 values of 46 nM and 25 nM, respectively, and a cellular IC50 value of 50 nM combined with an excellent pharmacokinetic profile in mice. The PARP domain of TNKS2 was cocrystallized with 66, and the X-ray structure was determined at 2.8 Å resolution in the space group P3221. The structure revealed that 66 binds to unique structural features in the extended adenosine binding pocket which forms the structural basis for the compound's high target selectivity and specificity. Our study provides a significantly optimized compound for targeting TNKS1/2 in vitro and in vivo.
Tankyrases 1 和 2（TNKS1/2）是有前途的药物靶点，可能应用于开发新型抗癌疗法。本研究基于 tankyrase 抑制剂 JW74（1）进行了重点结构-活性关系研究。对 1 进行化学模拟，改进了 1,2,4-三唑为核心的结构，得到了 4-{5-[(E)-2-{4-(2-氯苯基)-5-[5-(甲磺酰基)吡啶-2-基]-4H-1,2,4-三唑-3-基}乙烯基]-1,3,4-噁二唑-2-基}苯甲腈（G007-LK），这是一种有效的、符合“五规则”且代谢稳定的 TNKS1/2 抑制剂。G007-LK（66）对 tankyrases 1 和 2 具有高选择性，生化 IC50 值分别为 46 nM 和 25 nM，细胞 IC50 值为 50 nM，同时在小鼠中具有良好的药代动力学特征。TNKS2 的 PARP 结构域与 66 共结晶，X 射线结构在空间群 P3221 中以 2.8 Å 的分辨率确定。结构表明，66 结合到延长的腺苷结合口袋中的独特结构特征，这为化合物的高靶标选择性和特异性提供了结构基础。我们的研究提供了一种在体外和体内靶向 TNKS1/2 的显著优化的化合物。
