Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy
Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy
复制标题
DOI：
10.1016/j.ccell.2019.10.001
复制
发表时间：
2019-11-11
期刊：
影响因子：
50.3
通讯作者：
Abdulkadir, Sarki A.
中科院分区：
文献类型：
--
作者：
Han, Huiying;Jain, Atul D.;Abdulkadir, Sarki A.
直接靶向MYC并且在体内耐受性良好的小分子将提供宝贵的化学探针和潜在的抗癌治疗剂。我们开发了一系列小分子MYC抑制剂，这些抑制剂在细胞内参与MYC，破坏MYC/MAX二聚体，并损害MYC驱动的基因表达。所述化合物增强MYC在苏氨酸-58上的磷酸化，从而增加蛋白酶体介导的MYC降解。最初的先导药物MYC抑制剂361（MYCi 361）抑制了小鼠体内肿瘤生长，增加了肿瘤免疫细胞浸润，上调了肿瘤上的PD-L1，并使肿瘤对抗PD 1免疫疗法敏感。然而，361表现出狭窄的治疗指数。一种改进的类似物，MYCi 975显示出更好的耐受性。这些发现表明小分子MYC抑制剂作为化学探针和可能的抗癌治疗剂的潜力。
Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-moleculeMYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.