The Notch pathway regulates a diverse array of cell fate decisions, making it an enticing target in cancer therapy and regenerative medicine. During the early stages of Notch drug development, off-target toxicity precluded the approval of Notch inhibitors for the treatment of cancer. However, recent advances in our understanding of Notch structure and signaling have led to the development of several innovative Notch-based biotechnologies. In addition to new classes of inhibitors, pharmacological Notch activators have been shown to enhance osteogenesis and various aspects of T cell function. Furthermore, the mechanosensitive negative regulatory region (NRR) of the Notch receptor has been converted into synthetic Notch (synNotch) receptors with fully customizable signaling circuits. We review emergent Notch-based compounds, biologics, and cell therapies while highlighting the challenges and opportunities they face on the path to clinical development.

Notch 通路调节多种细胞命运决定，使其成为癌症治疗和再生医学中诱人的目标。在Notch药物开发的早期阶段，脱靶毒性阻碍了Notch抑制剂用于治疗癌症的批准。然而，最近我们对 Notch 结构和信号传导的理解取得了进展，导致了几种基于 Notch 的创新生物技术的发展。除了新型抑制剂外，药理学 Notch 激活剂已被证明可以增强成骨和 T 细胞功能的各个方面。此外，Notch 受体的机械敏感负调节区 (NRR) 已转化为具有完全可定制信号电路的合成 Notch (synNotch) 受体。我们回顾了新兴的基于 Notch 的化合物、生物制剂和细胞疗法，同时强调了它们在临床开发道路上面临的挑战和机遇。