肿瘤抑制因子TP53是人类癌症中的重要基因，因为在大多数肿瘤中突变，导致功能丧失或增益表型。突变的TP53就像一个癌基因，推动癌症进展并导致患者不良结局。突变p53在癌症中的作用已知三十多年，但目前尚无FDA批准的药物来解决这个问题。这个简短的历史观点突出了在靶向治疗p53时的启发性进展和挑战，特别是突变形式。文中着重介绍了一种恢复功能性p53通路的药物发现方法，这在多年前不是主流，没有人鼓励，没有出现在课本上，也没有被药物化学家所接受。在一些知识、临床医学家的兴趣和动力的推动下，作者展开了一条独特的研究路线，为人类癌症中TP53突变的功能性绕过提供了洞见。像突变的Ras蛋白一样，突变的p53在癌症中的治疗靶点具有基本意义，可能也值得像NCI的“Ras计划”一样进行“p53计划”。对于追求困难问题对于初学者来说有很多干劲，但是重要的解决方案是通过艰苦的工作和持久的努力才能发现的。希望通过这样的药物发现和开发工作，能够让患者获得一定的受益。© 2023年由美国癌症研究协会出版的作者。

Tumor suppressor TP53 is an important gene in human cancer because it is mutated in the majority of tumors, leading to loss-of-function or gain-of-function phenotypes. Mutated TP53 acts like an oncogene, driving cancer progression and causing poor patient outcomes. The role of mutated p53 in cancer has been known for over three decades, yet there is no FDA-approved drug to address the problem. This brief historical perspective highlights some of the insightful advances as well as challenges in therapeutic targeting of p53, especially the mutated forms. The article focuses on a functional p53 pathway restoration approach to drug discovery that years ago was not mainstream, encouraged by anyone, taught in textbooks, or embraced by medicinal chemists. With some knowledge, a clinician scientist's interest, and motivation, the author pursued a unique line of investigation leading to insights for functional bypass of TP53 mutations in human cancer. Like mutated Ras proteins, mutant p53 is fundamentally important as a therapeutic target in cancer and probably deserves a "p53 initiative" like the NCI's "Ras initiative." There is a link between naivete and enthusiasm for pursuing difficult problems, but important solutions are discovered through hard work and persistence. Hopefully, some benefit comes to patients with cancer from such drug discovery and development efforts.©2023 The Authors; Published by the American Association for Cancer Research.