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Updated: Feb 12, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Repositioning of Difluorinated Propanediones as Inhibitors of Histone Methyltransferases and their Biological
Tanushree Pal1, Asmita Sharda2,3, Bharat Khade2,3
1Bharati Vidyapeeth's College of Pharmacy, Department of Pharmaceutical Chemistry, Sector-8, C.B.D., Belapur, Navi Mumbai-400614, Maharashtra, India.
Background:
At present, 'pharmaco-epigenomics' constitutes the hope in cancer treatment owing to epigenetic deregulation- a reversible process and playing a role in malignancy.
Objective:
Chemotherapy has many limitations like host-tissue toxicity, drug resistance. Hence, it is imperative to unearth targets to better treat cancer. Here, we intend to repurpose a set of our previously synthesized difluorinated Propanediones (PR) as Histone lysine Methyltransferase inhibitors (HMTi).
Methods:
The cell lines of leukemic origin viz. histiocytic lymphoma (U937) and acute T-cell leukemia (JURKAT) were treated with PR-1 to 7 after docking studies with active pocket of HMT. The cell cycle analysis, in vitro methylation and cell proliferation assays were carried out to delineate their physiological role.
Results:
A small molecule PR-4, at 1 and 10µM, has shown to alter the methylation of histone H3 and H4 in both cell lines. Also, treatment shows an increase in G2/M population and a subsequent decrease in the G0/G1 population in U937. In JURKAT, an increase in both G2/M and S phase population was observed. The sub-G1 population showed a steady rise with increase in dose and prolonged time intervals in U937 and JURKAT cell lines. In SRB assay, the PR showed a cell growth of 42.6 and 53.4% comparable to adriamycin; 44.5 and 53.2% in U937 and JURKAT, respectively. The study suggests that PR-4 could emerge as a potential HMT inhibitor.
Conclusion:
The molecule PR-4 could be a lead in developing more histone lysine methyltransferases inhibitors with potential to be pro-apoptotic agents.
Insights
A novel difluorinated propanedione (PR-4) shows promise as a histone lysine methyltransferase inhibitor. This compound alters epigenetic markers and affects cell cycle progression, offering a potential new avenue for cancer treatment.
Area of Science:
- Epigenetics and Cancer Therapeutics
- Medicinal Chemistry
- Molecular Biology
Background:
- Epigenetic deregulation plays a key role in cancer development.
- Targeting reversible epigenetic modifications offers a promising strategy for cancer treatment.
- Conventional chemotherapy faces limitations such as toxicity and drug resistance.
Purpose of the Study:
- To repurpose synthesized difluorinated propanediones (PR) as histone lysine methyltransferase inhibitors (HMTi).
- To evaluate the potential of PR compounds as anti-cancer agents by targeting epigenetic mechanisms.
Main Methods:
- Docking studies were performed to identify potential HMT targets for PR compounds.
- Leukemic cell lines (U937 and JURKAT) were treated with PR-1 to PR-7.
- Cell cycle analysis, in vitro methylation assays, and cell proliferation assays (SRB) were conducted.
Main Results:
- PR-4 demonstrated the ability to alter histone H3 and H4 methylation in U937 and JURKAT cells.
- PR-4 treatment induced cell cycle arrest at the G2/M phase and increased sub-G1 population, indicating apoptosis.
- PR compounds exhibited significant anti-proliferative effects comparable to adriamycin.
Conclusions:
- PR-4 is identified as a potential histone lysine methyltransferase inhibitor.
- PR-4 exhibits pro-apoptotic properties and warrants further investigation.
- The findings suggest PR-4 as a lead compound for developing novel epigenetic-based cancer therapies.
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