1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Biological Chemistry &Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.
Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
Nat Chem Biol. 2014 Dec;10(12):1006-12. doi: 10.1038/nchembio.1658. Epub 2014 Oct 19.
Her3 (also known as ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be 'undruggable' using ATP-competitive small molecules because it lacks appreciable kinase activity. Here we report what is to our knowledge the first selective Her3 ligand, TX1-85-1, that forms a covalent bond with Cys721 located in the ATP-binding site of Her3. We demonstrate that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3-dependent cancer cell lines. Subsequent derivatization with a hydrophobic adamantane moiety demonstrates that the resultant bivalent ligand (TX2-121-1) enhances inhibition of Her3-dependent signaling. Treatment of cells with TX2-121-1 results in partial degradation of Her3 and serendipitously interferes with productive heterodimerization between Her3 with either Her2 or c-Met. These results suggest that small molecules will be capable of perturbing the biological function of Her3 and ∼60 other pseudokinases found in human cells.
Her3（也称为 ErbB3）属于表皮生长因子受体酪氨酸激酶，作为抗癌靶点已得到充分证实，但由于其激酶活性可忽略不计，因此被认为是“不可成药的”。在这里，我们报告了据我们所知的第一个选择性 Her3 配体 TX1-85-1，它与位于 Her3 的 ATP 结合位点的 Cys721 形成共价键。我们证明，Her3 的共价修饰可抑制 Her3 信号传导，但不会抑制某些 Her3 依赖性癌细胞系的增殖。随后用疏水性金刚烷部分进行衍生化，证明所得双价配体（TX2-121-1）增强了对 Her3 依赖性信号传导的抑制作用。用 TX2-121-1 处理细胞会导致 Her3 的部分降解，并意外地干扰 Her3 与 Her2 或 c-Met 之间的有效异二聚化。这些结果表明，小分子将能够扰乱 Her3 和人类细胞中约 60 种其他拟激酶的生物学功能。
