Discovery of a peptide proteolysis-targeting chimera (PROTAC) drug of p300 for prostate cancer therapy

Sep 21, 2026

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E1A-associated protein p300 (p300) is a key coactivator driving oncogenic signaling in prostate cancer, including castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Androgen deprivation therapy can eventually yield therapy-resistant and AR-independent disease states, motivating p300 blockade. An AI-assisted approach designs a peptide-based PROTAC targeting p300 and uses nano-selenium for delivery. The resulting p300 PROTAC degrades p300 in vitro and in vivo, suppresses tumors, and kills cancer cells across CRPC, AR-negative, and NEPC models.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages20

Reading Time50 min

AccessFree to download

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Articles Discovery of a peptide proteolysis-targeting chimera (PROTAC) drug of p300 for prostate cancer therapy Dize Zhang,a,d Bohan Ma,a,d,∗ Donghua Liu,a Wei Wu,b Tianyang Zhou,a Yibo Gao,a Cunli Yang,c YanlinJian,a Yizeng Fan,a Yuchen Qian,a Jian Ma,a Yang Gao,a Yule Chen,a Shan Xu,a and Lei Lia,∗∗ aDepartment of Urology, The First Afﬁliated Hospital, Xi’an Jiaotong University, Xi’an, China bDepartment of Neurosurgery, The First Afﬁliated Hospital, Xi’an Jiaotong University, Xi’an, China cDepartment of the Operating Theater, The First Afﬁliated Hospital, Xi’an Jiaotong University, Xi’an, China Summary Background 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 coactivator 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. Methods 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. Findings 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. Interpretation The design of peptide PROTAC drug targeting p300 is feasible and represents an efﬁcient therapeutic strategy for CRPC, AR-negative prostate cancer, and NEPC. Funding The funding details can be found in the Acknowledgements section. Copyright © 2024 The Author(s) . Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)). Keywords: p300; PROTAC; Peptide drug; Prostate cancer Introduction Despite signiﬁcant advancements in cancer treatment, it remains one of the most formidable challenges to human health.1,2 To address this, scientists are exploring new targets and treatment strategies to develop effective drugs for cancer therapy.3–5 The E1A-associated protein p300 (p300) has garnered increasing interest among researchers due to its pivotal role in gene transcription and its close association with tumor progression.6–10 Extensive research endeavors have consistently revealed the heightened expression of p300 in tumor cells, also in drug-resistant populations.11 Notably, p300 plays a pivotal role in the transcriptional activation of oncogenes, exerting substantial inﬂuence on various critical aspects of tumor biology including survival, proliferation, metastasis, immune evasion, drug resistance and so on.12–16 The p300 protein is comprised of several domains, including the acetyltransferase (HAT) domain17 and the bromodomain (BRD),18 which are crucial for its acetyltransferase activity. The HAT eBioMedicine 2024;105: 105212 Published Online xxx [https://doi.org/10](https://doi.org/10) . 1016/j.ebiom.2024 . 105212 *Corresponding author. **Corresponding author. E-mail [addresses:](addresses: bohanma@xjtu.edu.cn)[ bohanma@xjtu.edu.cn](addresses: bohanma@

FAQs

Why is p300 considered a therapeutic target in prostate cancer?

p300 promotes oncogenic signaling and acts as an important coactivator of the androgen receptor (AR), supporting prostate cancer progression. It also contributes to AR-independent oncogenic programs linked to NEPC.

How was the peptide PROTAC drug designed and delivered?

The study used AI-assisted design to develop a peptide-based PROTAC that targets p300. Nano-selenium was employed as a peptide drug delivery system.

What were the main experimental outcomes of the p300-targeting PROTAC?

The PROTAC effectively degraded p300 and showed cancer cell-killing activity in CRPC, AR-negative, and NEPC cells. In mouse models, it produced potent p300 degradation and tumor suppression in both AR-positive and AR-negative settings.

Sep 21, 2026

Uploaded by Noah