E1A 相关蛋白 p300 (p300) 已成为癌症治疗的一个有前景的靶标，因为它在促进包括前列腺癌在内的各种癌症的致癌信号通路中发挥着至关重要的作用。这种需求在前列腺癌中尤其重要。虽然雄激素剥夺疗法（ADT）已在前列腺癌中表现出良好的疗效，但其长期使用最终可能导致去势抵抗性前列腺癌（CRPC）和神经内分泌前列腺癌（NEPC）的发展。值得注意的是，p300 已被确定为雄激素受体 (AR) 的重要共激活剂，凸显了其在前列腺癌进展中的重要性。此外，最近的研究表明 p300 参与与 NEPC 相关的 AR 独立癌基因。因此，阻断p300可能成为解决CRPC和NEPC带来的挑战的有效治疗策略。我们采用人工智能辅助设计开发了一种基于肽的PROTAC（蛋白水解靶向嵌合体）药物，该药物以p300为目标，有效降解p300 在体外和体内利用纳米硒作为肽药物递送系统。我们的 p300 靶向肽 PROTAC 药物在 CRPC、AR 阴性和 NEPC 细胞中表现出有效的 p300 降解和癌细胞杀伤能力。这项研究证明了 p300 靶向药物在 NEPC 细胞中的功效。在 AR 阳性和 AR 阴性小鼠模型中，p300 PROTAC 药物显示出有效的 p300 降解和肿瘤抑制作用。针对 p300 的肽 PROTAC 药物的设计是可行的，代表了 CRPC、AR 阴性前列腺癌和癌症的有效治疗策略。 NEPC。资助详情可在致谢部分找到。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various cancers, including prostate cancer. This need is particularly significant in prostate cancer. While androgen deprivation therapy (ADT) has demonstrated promising efficacy in prostate cancer, its long-term use can eventually lead to the development of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Notably, p300 has been identified as an important co-activator of the androgen receptor (AR), highlighting its significance in prostate cancer progression. Moreover, recent studies have revealed the involvement of p300 in AR-independent oncogenes associated with NEPC. Therefore, the blockade of p300 may emerge as an effective therapeutic strategy to address the challenges posed by both CRPC and NEPC.We employed AI-assisted design to develop a peptide-based PROTAC (proteolysis-targeting chimera) drug that targets p300, effectively degrading p300 in vitro and in vivo utilizing nano-selenium as a peptide drug delivery system.Our p300-targeting peptide PROTAC drug demonstrated effective p300 degradation and cancer cell-killing capabilities in both CRPC, AR-negative, and NEPC cells. This study demonstrated the efficacy of a p300-targeting drug in NEPC cells. In both AR-positive and AR-negative mouse models, the p300 PROTAC drug showed potent p300 degradation and tumor suppression.The design of peptide PROTAC drug targeting p300 is feasible and represents an efficient therapeutic strategy for CRPC, AR-negative prostate cancer, and NEPC.The funding details can be found in the Acknowledgements section.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.