Department of Medicinal Chemistry, Drug and Biomaterial R&D, Genzyme Corp., 153 Second Avenue, Waltham, MA 02451, USA.
Bioorg Med Chem Lett. 2011 May 15;21(10):3050-6. doi: 10.1016/j.bmcl.2011.03.030. Epub 2011 Mar 16.
Novel benzofuran-2-carboxylic acids, exemplified by 29, 38 and 39, have been discovered as potent Pim-1 inhibitors using fragment based screening followed by X-ray structure guided medicinal chemistry optimization. The compounds demonstrate potent inhibition against Pim-1 and Pim-2 in enzyme assays. Compound 29 has been tested in the Ambit 442 kinase panel and demonstrates good selectivity for the Pim kinase family. X-ray structures of the inhibitor/Pim-1 binding complex reveal important salt-bridge and hydrogen bond interactions mediated by the compound's carboxylic acid and amino groups.
新型苯并呋喃-2-羧酸类化合物，例如化合物 29、38 和 39，是通过基于片段的筛选，随后进行 X 射线结构指导的药物化学优化，被发现为强效的 Pim-1 抑制剂。这些化合物在酶测定中表现出对 Pim-1 和 Pim-2 的强效抑制作用。化合物 29 已在 Ambit 442 激酶组中进行了测试，对 Pim 激酶家族表现出良好的选择性。抑制剂/Pim-1 结合复合物的 X 射线结构揭示了化合物的羧酸和氨基介导的重要盐桥和氢键相互作用。
