Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Eur J Med Chem. 2013 Jul;65:83-93. doi: 10.1016/j.ejmech.2013.03.035. Epub 2013 Apr 2.
Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development.
Mer 激酶的异常激活与多种人类癌症的发生有关，包括急性淋巴细胞白血病和髓系白血病、非小细胞肺癌和神经胶质瘤。我们发现了一类新的小分子 Mer 抑制剂——吡唑并嘧啶磺酰胺，它们能强烈抑制 Mer 的激酶活性。重要的是，这些化合物在 PatchXpress 测定中没有表现出明显的 hERG 活性。通过构效关系研究，确定 35（UNC1062）为一种有效的（IC50 = 1.1 nM）和选择性 Mer 抑制剂。当应用于活肿瘤细胞时，UNC1062 抑制 Mer 磷酸化和软琼脂中的集落形成。鉴于 Mer 作为治疗靶点的潜力，UNC1062 是进一步药物开发的有前途的候选药物。
