Tongji Hospital of Huazhong University of Science and Technology to License Novel ACSS3 Agonist Patent for Prostate Cancer Therapy

Recently, Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology released a public notice on the transformation of scientific and technological achievements, proposing to transfer its independently developed“An Agonist of Acyl-CoA Synthetase Short-Chain Family Member 3 and Its Application”The patent was transferred to the industry partner through agreement-based pricing. The transaction amount was the down payment.RMB 80,000, followed by superposition10% sales commission。

This patent identifies Compound 4 as a specific agonist of ACSS3 through homology modeling, computer-based virtual screening, and multiple rounds of cellular and animal experiments. This agonist fills the current therapeutic gap targeting ACSS3, providing a novel potential treatment option for patients with prostate cancer. The inventors of this patent areShen Ke and his team.

Prostate cancer, as a common malignant tumor in men, has a pathogenesis closely related to disorders of fatty acid metabolism, andAcyl-CoA Synthetase Short-Chain Family Member 3 (ACSS3)Plays a central role in this process.

ACSS3 is a key protein in the fatty acid metabolism pathway, with its structure featuring distinct functional domains:The first 116 amino acid residues constitute the N-terminus, while the region following residue 571 forms the C-terminus. The central segment, spanning residues 123 to 561, represents the core functional domain of the protein. Specifically, residues 227–230 comprise the coenzyme A-binding site, whereas residues 425–427 and 446–451 constitute key regions for ATP binding. These structural features provide the molecular basis for its regulation of fatty acid metabolism.

When the expression level of ACSS3 is significantly reduced in prostate cancer cells, this aberrant low expression disrupts the balance of fatty acid metabolism, leading to intracellular lipid droplet accumulation and elevated levels of triglycerides and cholesterol. These changes provide energy support for tumor cell proliferation and migration, thereby serving as a critical driver in the initiation, progression, and metastasis of prostate cancer. This mechanism is particularly pronounced in certain refractory subtypes of prostate cancer.

In the field of clinical treatment, prostate cancer presents numerous core challenges, with the inadequacy of precision medicine systems being particularly prominent. On one hand, there is significant inter-patient variability and strong tumor heterogeneity. Some patients exhibit a unique metabolic phenotype due to low ACSS3 expression, yet lack targeted diagnostic and therapeutic markers, leading to blind spots in treatment selection.

On the other hand, the symptoms of the disease are relatively insidious in the early stages, and most patients have progressed to the middle or late stages at the time of diagnosis. At this point, the tumor may have already undergone local invasion or distant metastasis, making it difficult for traditional treatment methods to achieve curative intervention.

Furthermore, patients are prone to relapse and drug resistance following treatment. Metabolic abnormalities associated with low ACSS3 expression enhance the survival capacity of tumor cells, leading to a gradual decline in the efficacy of conventional therapies. This further exacerbates the treatment burden on patients and increases prognostic risks. However, there is currently a lack of effective monitoring indicators and intervention strategies in clinical practice to address this challenge.

In current clinical protocols, although radical prostatectomy is applicable to patients with early-stage prostate cancer, the procedure is highly invasive and may lead to postoperative complications such as urinary incontinence and erectile dysfunction, which can significantly impair patients' quality of life. For intermediate-to-advanced stage or metastatic prostate cancer, surgery serves only as a palliative treatment modality and cannot inhibit systemic tumor progression.

As traditional cornerstone treatments, radiotherapy and chemotherapy suffer from a significant lack of selectivity between tumor and healthy tissues. While radiotherapy offers certain local control over tumors, it damages surrounding normal tissues, leading to adverse effects such as radiation cystitis and enteritis. Although chemotherapeutic agents can kill some rapidly proliferating tumor cells, they lack specificity; while targeting tumor cells, they also damage normal tissues such as bone marrow hematopoietic function and the gastrointestinal mucosa. This results in severe side effects, including myelosuppression, nausea and vomiting, and compromised immunity, making it difficult for most patients to tolerate the full course of treatment.

However, the application of traditional targeted therapy also presents significant limitations. Most targeted drugs currently used in clinical practice focus onClassic Targets Such as Androgen Receptors and Angiogenic Factors, targeted therapies against tumor metabolic pathways are extremely scarce, particularly showing almost no efficacy in prostate cancer subtypes driven by low ACSS3 expression. Some patients gradually progress to castration-resistant prostate cancer after androgen deprivation therapy, at which point the efficacy of traditional targeted drugs declines sharply, leaving patients with no available therapeutic options. There is an urgent need for novel targeted treatment strategies to fill this clinical gap.

The core value of this technology focuses onTarget Selection, R&D Technologies, and Mechanisms of ActionMultiple breakthroughs have ushered in a novel therapeutic paradigm for prostate cancer that combines innovation with practicality, demonstrating particularly significant advantages in clinical application.

Achieved precise breakthroughs in therapeutic targets.First Identification of Acyl-CoA Synthetase Short-Chain Family Member 3 as a Key Therapeutic Target in Prostate Cancer, in response to itsDownregulated Expression in Prostate Cancer CellsTo address this core pathological feature, a specific agonist was developed, successfully filling the global therapeutic gap for ACSS3-targeting drugs. Unlike traditional targeted therapies that focus on classic targets such as hormone receptors and angiogenesis, this achievement targets a key node in tumor metabolic pathways, providing a novel intervention strategy for refractory and drug-resistant prostate cancer that is insensitive to conventional treatments, thereby enabling precise targeting of tumor metabolic vulnerabilities.

In terms of technical approach, this patentEstablished a comprehensive system spanning from model development to experimental validation.ApplicationHomology Modeling Technology, successfully constructed a three-dimensional model of the human ACSS3 protein and identified its ATP-binding pocket as the core functional region.

Subsequently, a progressive virtual screening was conducted on two large compound libraries comprising over 500,000 compounds using professional tools. The screening scope was initially narrowed down through high-throughput screening, followed by stepwise precise screening using standard and high-precision modes. Concurrently, manual review was performed to assess the binding affinity, structural rationality, and drug-likeness of the compounds, ultimately yielding 10 candidate compounds.

Finally, validated through cell-based experiments.Only “Compound 4” was confirmed to exhibit significant ACSS3 agonist activity.. This approach not only ensures the breadth of the screening scope but also guarantees the specificity and reliability of target binding. Compound 4 can precisely bind to the ATP pocket of the ACSS3 protein, forming three stable hydrogen bonds and one π-π interaction, thereby tightly associating with the target protein. This specific interaction can effectively upregulate the expression level of ACSS3 protein in prostate cancer cells.

Therefore, this technology has successfully overcome the challenges of traditional therapies, namely “imprecision, significant side effects, and prominent drug resistance.” It precisely targets the ACSS3-mediated metabolic pathway, exerting its effects exclusively on prostate cancer cells with abnormally low ACSS3 expression. This approach minimizes damage to normal tissues, effectively reduces common adverse reactions associated with conventional treatments—such as myelosuppression and gastrointestinal responses—and significantly improves patients’ treatment tolerance.

Meanwhile, this agonistSpecifically targeting the prostate cancer subtype driven by low ACSS3 expression, providing a novel therapeutic option for refractory cases such as castration-resistant prostate cancer, significantly improving treatment response rates and extending survival in these patients. It is driving the transformation of prostate cancer management from “broad-spectrum intervention” to “precision targeting,” effectively addressing the unmet clinical need for effective treatments against such tumors.

Prostate cancer, as a highly prevalent malignant tumor in men, has seen the development of its therapeutic drugs into"Classic Marketed Drugs + Innovative Pipeline Drugs"dual-track landscape. The former, having undergone long-term clinical validation, serves as the current cornerstone of treatment; the latter focuses on innovative directions such as precision targeting, immune modulation, and metabolic intervention, holding promise for overcoming the bottlenecks of drug resistance and toxicity associated with conventional therapies.

Abiraterone Acetate (Brand Name: Zytiga):As a second-generation androgen synthesis inhibitor originally developed by Johnson & Johnson, it received FDA approval in 2011 and was included in China’s National Reimbursement Drug List in 2015. It primarily works by inhibiting the CYP17A1 enzyme, thereby blocking androgen synthesis in the adrenal glands, testes, and tumor tissues, thus cutting off the driving signals for tumor proliferation at the source. Its indications cover metastatic castration-resistant prostate cancer (mCRPC) and high-volume metastatic hormone-sensitive prostate cancer (mHSPC). Key clinical data show that in mCRPC patients who had previously failed chemotherapy, the median overall survival (OS) with combination therapy including prednisone reached 15.8 months, significantly superior to 11.2 months in the control group. In patients with high-volume mHSPC, 51% of patients remained alive at 54.8 months of follow-up, representing a 34% reduction in the risk of death compared to androgen deprivation therapy alone.

Enzalutamide (brand name: Xtandi):Jointly developed by Pfizer and Astellas, it received FDA approval in 2012 and was included in China’s National Reimbursement Drug List in 2019. As a second-generation androgen receptor (AR) antagonist, it exhibits 5–8 times higher affinity for AR than conventional agents and disrupts AR signaling through a triple mechanism: competitive binding, blockade of nuclear translocation, and inhibition of DNA binding. Its unique advantage lies in covering the entire disease continuum from non-metastatic castration-resistant prostate cancer (nmCRPC) to metastatic hormone-sensitive prostate cancer (mHSPC) and then to metastatic castration-resistant prostate cancer (mCRPC). In patients with high-risk nmCRPC, the median metastasis-free survival (MFS) reached 36.6 months, representing a 21.9-month improvement over the control group. In patients with mCRPC who had failed chemotherapy, overall survival (OS) reached 18.4 months, accompanied by improved pain relief rates and quality of life, without serious adverse events such as severe rash or seizures.

Docetaxel (brand name: Taxotere):Originally developed by Sanofi, it was launched globally in 1995 and approved for the indication of prostate cancer in 2004. It is the first chemotherapy agent proven to extend survival in patients with prostate cancer, working by stabilizing microtubule structures to block mitosis in tumor cells. It is primarily used for chemotherapy in high-volume metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). In patients with high-volume mHSPC, combination with androgen deprivation therapy achieved an overall survival (OS) of 57.6 months, reducing the risk of death by 20% compared with androgen deprivation therapy alone, and can rapidly control tumor burden and bone metastasis-related pain.

The First Affiliated Hospital of Guangzhou Medical University:Targeted exosome drugs, with core design as“Aptamer–Exosome–siRNA” Complex System. The drug is administered via peripheral veins and can specifically bind to prostate cancer cells (PC3, DU145) without interacting with normal BPH cells. In cell experiments, its tumor inhibition effect was more than doubled compared to inhibiting a single gene alone; in animal experiments, it significantly reduced tumor volume with a continuous downward trend, while reducing non-specific damage through targeted delivery.

Shanghai Sixth People's Hospital:PSMA-Targeted Drug-Loaded Nanoliposomes,Using dipalmitoylphosphatidylcholine, cholesterol, and DSPE-PEG-folate as carriers, docetaxel was loaded via the thin-film hydration-sonication-extrusion method, resulting in an average particle size of 95–100 nm and a drug encapsulation efficiency exceeding 90%. Its core advantage lies in the specific binding of folate (FA) to PSMA, which is highly expressed on prostate cancer cells, thereby enabling active targeted delivery. Additionally, it features acid-sensitive release properties, achieving a cumulative release rate of 84.3% over 72 hours in the acidic tumor microenvironment (pH 5.6). In cellular experiments, the uptake of this liposome by LNCaP cells was six times higher than that of non-targeted formulations. In animal studies, the tumor inhibition rate exceeded 55%, with no significant structural damage observed in major organs (heart, liver, spleen, lungs, and kidneys) and normal hepatic and renal function indicators.

Zhongnan Hospital of Wuhan University:Dual-target combination drug,Composed of a FEN1 inhibitor (FEN1-IN-4) and a TXN antioxidant system inhibitor (TRi-1), preferably at a molar ratio of 4:1. This drug exerts a synergistic effect through dual inhibition of the “DNA replication repair pathway + oxidative stress pathway,” significantly suppressing tumor growth and reducing the Ki-67-positive cell rate, with no evident pathological damage to major organs and normal serum biochemical indices.

In the innovative exploration of prostate cancer treatment, breakthroughs are continuously being made toward precision, targeting, and reduced toxicity, with classic drugs serving as the cornerstone. This has enabled the development of more targeted treatment regimens for prostate cancer patients with different subtypes and disease stages, while also fostering a favorable landscape of diversified deployment for domestically developed original innovative drugs in the prostate cancer diagnosis and treatment sector.

In the future, as these projects continue to advance from basic research to clinical translation, they will further enrich treatment options for prostate cancer, improve patients’ quality of life, and extend survival, thereby bringing new clinical hope for the precision diagnosis and treatment of male urological malignancies.