Drug Discovery Research, Carna Biosciences, Inc., 3rd Floor, BMA, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.
Bioorg Med Chem Lett. 2012 Jan 1;22(1):591-6. doi: 10.1016/j.bmcl.2011.10.076. Epub 2011 Oct 30.
Fragment-based lead discovery is a new approach for lead generation that has emerged in the past decade. Because the initial fragments identified in the fragment screening typically show weak binding affinity, an intensive medicinal chemistry effort would be required to grow initial fragments into a potential lead compound. Here we demonstrate a kinase focused evolved fragment (KFEF) library, constructed by click chemistry-based fragment assembly, that is a valuable source of kinase inhibitors. This combinatorial assembly of two fragments, kinase-privileged alkyne fragments and diversified azide fragments, by two cycloaddition reactions shows a unique potential for the one-step synthesis of structurally diverse evolved fragments. The screening of this triazole-based KFEF library allowed the rapid identification of potent lead candidates for FLT3 and GSK3β kinase.
基于片段的先导化合物发现是一种在过去十年中出现的新的先导化合物生成方法。由于在片段筛选中最初鉴定的片段通常显示出较弱的结合亲和力，因此需要进行密集的药物化学研究，才能将最初的片段发展成有潜力的先导化合物。在这里，我们展示了一个基于点击化学的片段组装构建的激酶定向进化片段（KFEF）文库，它是激酶抑制剂的有价值的来源。通过两步环加成反应将两个片段（激酶优势炔片段和多样化的叠氮片段）组合在一起，这种组合方式为一步合成结构多样的进化片段提供了独特的潜力。对这个基于三唑的 KFEF 文库的筛选，使得能够快速鉴定出 FLT3 和 GSK3β 激酶的有效先导化合物候选物。
