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Implantable HDAC-inhibiting chemotherapeutics derived from hydrophobic amino acids for localized anticancer therapy
Somnath Dharmaraj Bhagat1, Abhishek Chanchal, Mansi Gujrati
1Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhopal, Madhya Pradesh 462066, India. asrivastava@iiserb.ac.in.
Abstract:
Epigenetic targeting of different cancers by inhibiting particular histone deacetylase (HDAC) isozymes is a promising treatment approach against cancer. Development of locally-implantable molecular inhibitors of HDAC (henceforth called HDACi) promises high tumour site concentration and reduced systemic degradation of the HDACi. Herein, we report the design of such implantable HDACi based on amphiphilic derivatives of hydrophobic amino acids endowed with a hydroxamic acid (hxa)-based zinc-binding residue. The amino acids present in HDACi influenced the HDAC isozyme that could be inhibited most effectively; the l-phenylalanine derivative 4e inhibited the HDAC6 isozyme most potently (IC50 ∼ 88 nM), while the l-isoleucine derivative 4h was most effective against the isozyme HDAC2 (IC50 ∼ 94 nM). We also noticed that the l-Phe derivative 4e was up to 5× more potent towards inhibiting HDAC6 than its optical antipode 4f derived from d-Phe. This was rationalized in terms of the varying extent of penetration of the enantiomeric inhibitors inside the catalytic tunnel of the enzyme. Since the isozymes HDAC6 and HDAC2 are overexpressed in different cancer cells, 4e and 4h elicited selective anticancer activity in different cancer cell lines. Additive therapeutic action of the combination therapy of 4e and 4h was observed on lung cancer cells that overexpress both these isozymes. Further, 4e formed implantable self-assembled hydrogels that achieved sustained and selective killing of cancer cells in the vicinity of implantation.
Insights
New implantable histone deacetylase inhibitors (HDACi) show promise for cancer treatment. These novel compounds selectively target cancer cells, with one derivative forming hydrogels for sustained drug delivery and tumor site concentration.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Epigenetic regulation via histone deacetylase (HDAC) inhibition is a key strategy in cancer therapy.
- Developing localized HDAC inhibitors (HDACi) can enhance tumor concentration and reduce systemic side effects.
- Amphiphilic derivatives of hydrophobic amino acids with hydroxamic acid (hxa) moieties offer a novel approach for HDACi design.
Purpose of the Study:
- To design and synthesize implantable HDAC inhibitors based on amino acid derivatives.
- To evaluate the inhibitory activity and selectivity of these compounds against specific HDAC isozymes.
- To assess the anticancer efficacy and drug delivery potential of these novel HDACi.
Main Methods:
- Synthesis of amphiphilic amino acid derivatives functionalized with hydroxamic acid (hxa) groups.
- Enzymatic assays to determine the inhibitory potency (IC50) against different HDAC isozymes (e.g., HDAC6, HDAC2).
- In vitro evaluation of selective anticancer activity in various cancer cell lines and assessment of hydrogel formation for drug delivery.
Main Results:
- The l-phenylalanine derivative (4e) potently inhibited HDAC6 (IC50 ~ 88 nM), while the l-isoleucine derivative (4h) was most effective against HDAC2 (IC50 ~ 94 nM).
- Enantiomeric specificity was observed, with derivative 4e showing higher potency against HDAC6 than its d-phenylalanine counterpart (4f).
- Derivatives 4e and 4h demonstrated selective anticancer activity in cell lines overexpressing their respective target HDAC isozymes, with synergistic effects observed in lung cancer cells.
Conclusions:
- Novel implantable HDAC inhibitors derived from amino acids exhibit potent and selective inhibition of specific HDAC isozymes.
- The design allows for targeted cancer therapy, with potential for enhanced efficacy and reduced systemic toxicity.
- Implantable hydrogel formulations of these HDACi offer a promising strategy for sustained, localized cancer treatment.
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