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HDAC3 is a potential validated target for cancer: An overview on the benzamide-based selective HDAC3 inhibitors
Nilanjan Adhikari1, Sk Abdul Amin1, Prakruti Trivedi2
1Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P. O. Box 17020, Jadavpur University, Kolkata, 700032, West Bengal, India.
Abstract:
Deacetylation of histones by histone deacetylase 3 (HDAC3) is involved in apoptosis, cellular progression and DNA damage. Due to the overexpression of HDAC3 in a variety of cancers, it is implicated to be a crucial validated target for cancer. Therefore, HDAC3 selective inhibitors have roles to play in combating these cancers. Nowadays, compounds comprising benzamide functionality as zinc binding group (ZBG) have been emerged out to be highly effective and selective HDAC3 inhibitors. In this article, QSAR and QAAR studies have been conducted on diverse benzamide-derived HDAC3 inhibitors as the first initiative to explore the designing strategies of higher active and selective HDAC3 inhibitors over HDAC1 and HDAC2. QSAR models reveal that molecular size and shape along with the steric effect should have to be optimized to achieve higher HDAC3 inhibition. QAAR models reflect that modification/substitution at the benzamide scaffold should be optimized in such a way so that these molecules possess lower steric bulk along with nonpolar features for achieving higher HDAC3 selectivity over HDAC1 and HDAC2. However, the importance of spiro hydrophobic cap group, as well as electron withdrawing fluorine group at the benzamide scaffold, should be well-accounted for retaining higher HDAC3 selectivity over HDAC1. Moreover, less polar and less hydrophobic benzamides are preferred for HDAC3 selectivity over HDAC2. This detailed structural exploration will surely unveil a new vista of designing highly potent and selective benzamide-based HDAC3 inhibitors that may be a crucial weapon to battle against a variety of cancers.
Insights
Histone deacetylase 3 (HDAC3) inhibitors are crucial for cancer treatment. This study uses QSAR and QAAR to design potent and selective benzamide-based HDAC3 inhibitors, optimizing molecular features for enhanced efficacy and reduced side effects.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Cancer Research
Background:
- Histone deacetylase 3 (HDAC3) plays a role in apoptosis, cell progression, and DNA damage.
- Overexpression of HDAC3 is linked to various cancers, making it a validated therapeutic target.
- Selective HDAC3 inhibitors are essential for cancer therapy.
Purpose of the Study:
- To explore design strategies for potent and selective benzamide-derived HDAC3 inhibitors.
- To investigate structure-activity and structure-selectivity relationships for HDAC3 inhibition over HDAC1 and HDAC2.
- To guide the development of novel anticancer agents targeting HDAC3.
Main Methods:
- Quantitative Structure-Activity Relationship (QSAR) studies on benzamide-derived HDAC3 inhibitors.
- Quantitative Activity-Activity Relationship (QAAR) analysis to assess selectivity over HDAC1 and HDAC2.
- Detailed structural analysis of key functional groups influencing inhibition and selectivity.
Main Results:
- QSAR models indicate that optimizing molecular size, shape, and steric effects enhances HDAC3 inhibition.
- QAAR models suggest that reduced steric bulk and nonpolar features on the benzamide scaffold improve selectivity over HDAC1 and HDAC2.
- Specific structural features like spiro hydrophobic caps and electron-withdrawing fluorine groups are crucial for HDAC1 selectivity, while less polar/hydrophobic benzamides favor HDAC2 selectivity.
Conclusions:
- Structural modifications of benzamide scaffolds can yield highly potent and selective HDAC3 inhibitors.
- Understanding structure-activity and structure-selectivity relationships is key to designing effective anticancer drugs.
- These findings provide a foundation for developing novel benzamide-based HDAC3 inhibitors for cancer treatment.
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