Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2013 Jun 1;23(11):3358-63. doi: 10.1016/j.bmcl.2013.03.090. Epub 2013 Apr 1.
The M2 isoform of pyruvate kinase is an emerging target for antitumor therapy. In this letter, we describe the discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as potent and selective PKM2 activators which were found to have a novel binding mode. The original lead identified from high throughput screening was optimized into an efficient series via computer-aided structure-based drug design. Both a representative compound from this series and an activator described in the literature were used as molecular tools to probe the biological effects of PKM2 activation on cancer cells. Our results suggested that PKM2 activation alone is not sufficient to alter cancer cell metabolism.
丙酮酸激酶 M2 同工酶是抗肿瘤治疗的一个新兴靶点。在这封信中，我们描述了发现 2-((1H-苯并[d]咪唑-1-基)甲基)-4H-吡啶并[1,2-a]嘧啶-4-酮作为强效和选择性的 PKM2 激活剂，它们具有新颖的结合模式。从高通量筛选中鉴定出的原始先导化合物通过基于计算机的结构药物设计被优化成有效的系列。该系列中的代表性化合物和文献中描述的一种激活剂都被用作分子工具来研究 PKM2 激活对癌细胞的生物学影响。我们的结果表明，单独激活 PKM2 不足以改变癌细胞的代谢。
