Aurigene Discovery Technologies Limited, Bangalore, India.
Front Immunol. 2022 May 2;13:752065. doi: 10.3389/fimmu.2022.752065. eCollection 2022.
Pioneering success of antibodies targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has changed the outlook of cancer therapy. Although these antibodies show impressive durable clinical activity, low response rates and immune-related adverse events are becoming increasingly evident in antibody-based approaches. For further strides in cancer immunotherapy, novel treatment strategies including combination therapies and alternate therapeutic modalities are highly warranted. Towards this discovery and development of small molecule, checkpoint inhibitors are actively being pursued, and the efforts have culminated in the ongoing clinical testing of orally bioavailable checkpoint inhibitors. This review focuses on the small molecule agents targeting PD-1 checkpoint pathway for cancer immunotherapy and highlights various chemotypes/scaffolds and their characterization including binding and functionality along with reported mechanism of action. The learnings from the ongoing small molecule clinical trials and crucial points to be considered for their clinical development are also discussed.
靶向免疫检查点的抗体（如程序性细胞死亡蛋白 1 (PD-1) 和细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4)）的开创性成功改变了癌症治疗的前景。尽管这些抗体表现出令人印象深刻的持久临床活性，但在抗体治疗方法中，低反应率和免疫相关不良事件变得越来越明显。为了在癌症免疫治疗方面取得进一步进展，包括联合治疗和替代治疗方式在内的新型治疗策略是非常必要的。为此，小分子检查点抑制剂的发现和开发正在积极进行中，这些努力的成果是正在进行的口服生物可利用检查点抑制剂的临床测试。本文重点介绍了针对癌症免疫治疗的靶向 PD-1 检查点途径的小分子药物，并强调了各种化学型/支架及其特性，包括结合和功能，以及报道的作用机制。本文还讨论了正在进行的小分子临床试验的经验教训以及在其临床开发中需要考虑的要点。
