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.

The mechanistic (formally “mammalian”) target of rapamycin (mTOR) pathway serves as a crucial regulator of various biological processes such as cell growth and cancer progression. In bladder cancer, recent discoveries showing the cancer-promoting role of mTOR complex 1 have attracted wide attention. However, the regulation of mTOR signaling in bladder cancer is complicated and the underlying mechanism remains elusive. Here, we report that the deubiquitinating enzyme, ovarian tumor domain-containing protein 5 (OTUD5), can activate the mTOR signaling pathway, promote cancer progression, and show its oncogenic potential in bladder cancer. In our study, we found that OTUD5 deubiquitinated a RING-type E3 ligase, RNF186, and stabilized its function. In addition, the stabilization of RNF186 further led to the degradation of sestrin2, which is an inhibitor of the mTOR signaling pathway. Together, we provide novel insights into the pathogenesis of bladder cancer and first prove that OTUD5 can promote bladder cancer progression through the OTUD5-RNF186-sestrin2-mTOR axis, which may be exploited in the future for the diagnosis and treatment of this malignancy.

Defects in homologous recombination repair (HR) make cells highly susceptible to PARP inhibitors. However, the limited efficacy of PARP inhibitors in targeting HR wild-type tumors restricts their broad utility in cancer treatment. Clinical trials of PARP inhibitors have revealed greater efficacy in men with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA2 mutations compared to those with mutations in other HR genes. To address this, we developed a peptide-based proteolysis-targeting chimera (PROTAC) drug that specifically targets BRCA2, leading to its degradation in a DDB1-dependent manner. The interaction between DDB1 and BRCA2 facilitated nuclear accumulation of the BRCA2 peptide PROTAC (BPD), thereby promoting BRCA2 degradation in response to DNA damage. Combining BPD treatment with PARP inhibitors promoted cell death in prostate cancer cells and induced tumor regression in animal models. These findings suggest that development of a PROTAC drug targeting BRCA2 offers a promising strategy in combination with PARP inhibitor therapy for treating cancers without HR defects. This approach holds potential for expanding the therapeutic application of PARP inhibition for prostate cancer management.

Polybromo 1 (PBRM1) inactivating mutations are associated with clinical benefit from immune checkpoint inhibitor treatments in clear cell renal cell carcinoma (ccRCC). However, whether targeting PBRM1 has the potential to enhance immunotherapy efficacy in patients with wild‐type PBRM1 and the upstream pathways that regulate PBRM1 protein stability remain unclear. Here, it is demonstrated that PBRM1 knockdown induced M1 macrophage polarization and infiltration, which enhanced the efficacy of anti‐PD‐1 immunotherapy in RCC. Meanwhile, CDC20 catalyzes K27 ubiquitination of PBRM1 and promotes its degradation via p62‐mediated selective autophagy. A bicyclic peptide (PB1‐p62) is designed and constructed to target PBRM1 and p62, thereby promoting the degradation of PBRM1. As a result, the efficacy of anti‐PD‐1 immunotherapy is enhanced, leading to improved overall survival rates in syngeneic mouse tumor models. Overall, this finding suggest the clinical application of PB1‐p62 and provide a novel approach for enhancing the effectiveness of immunotherapy in RCC patients with wild‐type PBRM1.

Acute lymphoblastic leukemia (ALL) is a highly heterogeneous hematologic malignancy with poor prognosis in refractory and relapsed cases. Aurora kinase B (AURKB), a member of the Aurora kinase family, is markedly overexpressed in ALL patients with cytogenetic abnormalities and is associated with unfavorable clinical outcomes. Targeting AURKB represents a promising therapeutic approach to address this unmet clinical need. This study aimed to develop and validate a novel, selective degradation strategy against AURKB in ALL, utilizing artificial intelligence-assisted drug design to create a peptide-based degrader. The goal was to demonstrate the efficacy of this degrader in reducing AURKB expression and suppressing leukemic cell growth. We performed database analyses and confirmed AURKB overexpression in patient-derived ALL samples. Using AI-assisted design, we developed ATPD (AURKB Targeting Peptide Degrader), a selective peptide-based degrader of AURKB. The activity of ATPD was evaluated through in vitro cell proliferation assays, in vivo leukemia models, and ex vivo cytotoxicity tests using primary ALL cells. ATPD effectively induced the degradation of AURKB and significantly inhibited the proliferation of ALL cells both in vitro and in vivo. Furthermore, ATPD exhibited potent cytotoxic activity against primary leukemic cells derived from ALL patients, B-All PDX, and mini-PDX models. Our findings demonstrate that ATPD is the first AI-designed, selective AURKB degrader with potent anti-leukemic activity. This study highlights ATPD's potential as a novel, precise therapeutic strategy for the treatment of ALL, addressing a critical gap in managing refractory and relapsed disease.

Hypoxia inducible factor 2α (HIF2α) is a major oncogenic driver in clear cell renal cell carcinoma (ccRCC). HIF2α is upregulated by von Hippel-Lindau (VHL) gene loss-of-function mutations in ccRCC. Deubiquitinating enzymes (DUBs) have emerged as key regulators of oncoprotein stability, but which DUBs sustain HIF2α accumulation in ccRCC remains unknown. Our study sought to systematically identify DUBs that stabilize HIF2α regardless of VHL status. We selected three ccRCC cell lines with distinct VHL gene statuses, and 15 DUB inhibitors were applied to screen for DUBs that regulate the degradation of the HIF2α protein in ccRCC regardless of VHL gene status. Coimmunoprecipitation (Co-IP) and mass spectrometry (MS) were used to verify the interactions between DUBs and the HIF2α protein. In our study, the PR-619 inhibitor caused a decrease in the HIF2α protein level in 786-O, OS-RC-2, and SW839 cells, and MG132 treatment increased HIF2α protein expression after PR-619 treatment. Furthermore, the MS, Co-IP and Western blotting results revealed that ubiquitin-specific peptidase 10 (USP10) is a DUB that binds to HIF2α and that depletion of USP10 leads to HIF2α downregulation through promotion of HIF2α ubiquitination. We also confirmed that USP10 expression was upregulated in kidney cancer and had a positive correlation with HIF2α expression in RCC patient samples. Our results suggest that USP10 promotes HIF2α stability.