新型MYC蛋白小分子抑制剂可抑制肿瘤生长

研究人员研发了一系列小分子MYC抑制剂，它们与细胞内的MYC结合，破坏MYC/MAX二聚体并抑制MYC驱动的基因表达。这些化合物增强了MYC上第58位苏氨酸上的磷酸化，因此增加了蛋白酶体介导的MYC降解。MYC抑制剂361（MYCi361）抑制了小鼠体内肿瘤的生长，增加了肿瘤免疫细胞的浸润，上调了肿瘤上的PD-L1，并使肿瘤对PD1免疫疗法敏感。然而，361表现出局限性治疗指数。改进的类似物MYCi975显示出更好的耐受性。这些发现体现了小分子MYC抑制剂作为化学探针和潜在抗癌治疗药物的潜力。

据介绍，直接靶向MYC并在体内也具有良好耐受性的小分子将成为宝贵的化学探针和潜在的抗癌治疗药物。

附：英文原文

Title: Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

Author: Huiying Han, Atul D. Jain, Mihai I. Truica, Javier Izquierdo-Ferrer, Jonathan F. Anker, Barbara Lysy, Vinay Sagar, Yi Luan, Zachary R. Chalmers, Kenji Unno, Hanlin Mok, Rajita Vatapalli, Young A. Yoo, Yara Rodriguez, Irawati Kandela, J. Brandon Parker, Debabrata Chakravarti, Rama K. Mishra, Gary E. Schiltz, Sarki A. Abdulkadir

Issue&Volume: October 31, 2019

Abstract: 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-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.

DOI: 10.1016/j.ccell.2019.10.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30439-8#%20