ArticleJournal of advanced research2023
Rational design of synthetically tractable HDAC6/HSP90 dual inhibitors to destroy immune-suppressive tumor microenvironment.
Article in Journal of advanced research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 29 citations in OpenAlex.
- The histone deacetylase family in health and disease.Signal transduction and targeted therapy · 2026Review
- Deciphering the tubulin code: roles and mechanisms of microtubule post-translational modifications in gastrointestinal tumors: a narrative review.Journal of gastrointestinal oncology · 2026Review
- Fundamentals and emerging frontiers in p53-targeted drug development.Biochemistry and biophysics reports · 2026Review
- Recent progress in the development of HSP90 inhibitors: structure-activity relationship and biological evaluation studies.Molecular diversity · 2026Review
- Role of HDAC6 in carcinomas.Discover oncology · 2026Review
- Identification of Potential Dual HDAC6 and HSP90 Inhibitors for the Treatment of Cancer using Molecular Docking, Molecular Dynamics and MM/PBSA Studies: A ComprehensiveMedicinal chemistry (Shariqah (United Arab Emirates)) · 2026Article
- Recent progress and structural insights of potential Hsp90 inhibitors as anticancer agents.Molecular diversity · 2025Review
- Histone deacetylase 6: A new player in oxidative stress‑associated disorders and cancers (Review).International journal of molecular medicine · 2025Review
- Aurantio-obtusin modulates Wilms Tumour 1 within the breast tumour microenvironment reducing immunosuppression and tumour growth.Cell communication and signaling : CCS · 2025Article
- Repurposing Linezolid in Conjunction with Histone Deacetylase Inhibitor Access in the Realm of Glioblastoma Therapies.Journal of medicinal chemistry · 2025Article
- Searching for Novel HDAC6/Hsp90 Dual Inhibitors with Anti-Prostate Cancer Activity: In Silico Screening and In Vitro Evaluation.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer.Pharmaceutics · 2023Review
- Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies.Molecules (Basel, Switzerland) · 2023Article
- A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma.Open medicine (Warsaw, Poland) · 2023Article
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionThe tumor microenvironment is mainly flooded with immunosuppressive cells and inhibitory cytokines, resulting in the inability of effective immune cells to infiltrate and recognize tumors and even the loss of anti-cancer ability.
objectivesWe propose a novel HDAC6/HSP90 dual inhibitory strategy as well as a chemoimmunotherapeutic agent that does not only kill tumor cells but also destroys the tumor microenvironment and enhances anti-cancer immunity.
methodsA hybrid scaffold construction approach was leveraged to furnish a series of rationally designed resorcinol-based hydroxamates as dual selective HDAC6/HSP90 inhibitors. The drug design campaign commenced with a fragment recruitment process to pinpoint validated structural units to inhibit HDAC6 and HSP90, followed by their installation in flexible HDAC inhibitory templates via an efficient and facile multistep synthetic route. Subsequent evaluations identified a strikingly potent selective HDAC6/HSP90 dual inhibitor (compound 17) via molecular and biological analysis in vitro and in vivo.
resultsCompound 17 exhibited not only direct cytotoxicity to cancer cells but also downregulated immune checkpoints (PD-L1 and IDO) expression in tumors via the inhibition of STAT1 pathway and degradation of oncogene proteins (Src, AKT, Rb, and FAK), leading to in vivo tumor growth inhibition. These multiple effects enabled the effector T cells to largely infiltrate into the tumor region and release granzyme B to kill cancer cells. In addition, compound 17 also decreased TGF-β secretion from normal cells, resulting in the systemic reduction of immunosuppressive regulatory T cells. Delightfully, a cocktail treatment of compound 17 and anti-PD-1 antibodies demonstrated synergistic efficacy to eliminate solid tumors with 83.9% of tumor growth inhibition.
conclusionIn summary, the impressive activity profile of compound 17, as an effective anticancer agent and a potential immunosensitizer, forecasts the application of HDAC6/HSP90 dual inhibitory strategy to overcome the immunosuppressive tumor microenvironment.
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