A MULTISCALE APPROACH TO TARGET THE ACHILLES HEEL OF P53 CANCER MUTANTS

总结 p53可以说是人类中最重要的肿瘤抑制蛋白之一。近50% 在所有人类癌症中，发现p53主要由于单点突变而无功能。的 本提案的主要目标是详细了解最常见的 p53癌基因突变对蛋白质结构和动力学的影响，并利用一种新的 鉴定能够重新激活不稳定的p53的小分子的计算方法 癌症突变体-一种方法，代表了一种有前途的新方法，以药物发现。我们的目标 为了扩展我们对截短和全长p53的结构动力学的理解， 最先进的分子动力学模拟，以发现新的药物口袋， 尚未被实验表征。随后，我们计划使用这种新的结构 识别具有新作用机制的小分子并揭示新潜力的信息 针对这一重要转录因子的治疗途径。

SUMMARY p53 is arguably one of the most important tumor suppressor proteins in humans. In almost 50% of all human cancers, p53 is found to be nonfunctional mostly due to single point mutations. The primary goals of this proposal are to gain a detailed understanding of the effect of most-frequent p53 cancer mutations on the protein structure and dynamics, and to leverage a novel computational methodology that identifies small molecules able to reactivate destabilized p53 cancer mutants—a method that represents a promising new approach to drug discovery. We aim to extend our understanding of the structural dynamics of truncated and full-length p53 with state- of-the-art molecular dynamics simulations in order to discovery novel druggable pockets that have not yet been experimentally characterized. Subsequently we plan to use this new structural information to identify small molecules with novel mechanisms of action and reveal new potential therapeutic avenues targeting this vital transcription factor.