Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy.
J Med Chem. 2010 Oct 28;53(20):7296-315. doi: 10.1021/jm100504d.
Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considered a potential target for anticancer therapy. We previously reported that pyrrolopyridinones (e.g., 1) are potent and selective inhibitors of Cdc7 kinase, with good cellular potency and in vitro ADME properties but with suboptimal pharmacokinetic profiles. Here we report on a new chemical class of 5-heteroaryl-3-carboxamido-2-substituted pyrroles (1A) that offers advantages of chemistry diversification and synthetic simplification. This work led to the identification of compound 18, with biochemical data and ADME profile similar to those of compound 1 but characterized by superior efficacy in an in vivo model. Derivative 18 represents a new lead compound worthy of further investigation toward the ultimate goal of identifying a clinical candidate.
Cdc7 丝氨酸/苏氨酸激酶是真核生物 DNA 合成的关键调节剂。通过 siRNA 或原型小分子抑制 Cdc7 会导致肿瘤细胞发生 p53 非依赖性凋亡，而在原代成纤维细胞中可逆地阻止细胞周期进程。这意味着 Cdc7 激酶可以被认为是一种潜在的抗癌治疗靶点。我们之前曾报道过吡咯并吡啶酮（例如 1）是 Cdc7 激酶的有效且选择性抑制剂，具有良好的细胞效力和体外 ADME 特性，但药代动力学特性不理想。在这里，我们报告了一类新的 5-杂芳基-3-羧酰胺-2-取代吡咯（1A）的化学类别，其具有化学多样化和合成简化的优势。这项工作确定了化合物 18，其生化数据和 ADME 特征与化合物 1 相似，但在体内模型中表现出更好的疗效。衍生物 18 代表了一种新的先导化合物，值得进一步研究，以最终确定一个临床候选药物。
