Overexpression of coactivator associated arginine methyltransferase 1 (CARM1) is associated with various diseases including cancer. Therefore, CARM1 has emerged as an attractive therapeutic target and a drug response biomarker for anticancer drug discovery. However, the development of conventional CARM1 inhibitors has been hampered by their limited clinical efficacy, acquired resistance, and inability to inhibit nonenzymatic functions of CARM1. To overcome these challenges, new strategies such as isoform-selective inhibitors, dual-acting inhibitors, targeted protein degradation technology (e.g., PROTACs), and even activators, are essential to enhance the anticancer activity of CARM1 modulators. In this perspective, we first summarize the structure and biofunctions of CARM1 and its association with cancer. Next, we focus on the recent advances in CARM1 modulators, including isoform-selective CARM1 inhibitors, dual-target inhibitors, PROTAC degraders, and activators, from the perspectives of rational design, pharmacodynamics, pharmacokinetics, and clinical status. Finally, we discuss the challenges and future directions for CARM1-based drug discovery.

中文翻译：

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靶向共激活因子相关精氨酸甲基转移酶 1 （CARM1） 的小分子调节剂作为癌症治疗的治疗剂：当前的药物化学见解和新兴机遇


共激活因子相关精氨酸甲基转移酶 1 （CARM1） 的过表达与包括癌症在内的多种疾病有关。因此，CARM1 已成为一种有吸引力的治疗靶点和抗癌药物发现的药物反应生物标志物。然而，传统 CARM1 抑制剂的开发受到其临床疗效有限、获得性耐药以及无法抑制 CARM1 非酶功能的阻碍。为了克服这些挑战，亚型选择性抑制剂、双效抑制剂、靶向蛋白质降解技术（例如 PROTAC）甚至激活剂等新策略对于增强 CARM1 调节剂的抗癌活性至关重要。从这个角度来看，我们首先总结了 CARM1 的结构和生物功能及其与癌症的关联。接下来，我们从合理设计、药效学、药代动力学和临床状态的角度重点介绍 CARM1 调节剂的最新进展，包括亚型选择性 CARM1 抑制剂、双靶点抑制剂、PROTAC 降解剂和激活剂。最后，我们讨论了基于 CARM1 的药物发现的挑战和未来方向。