Histone deacetylase inhibitors (HDACIs). Structure—activity relationships: history and new QSAR perspectives

Abstract

Histone deacetylase (HDAC) inhibition is a recent, clinically validated therapeutic strategy for cancer treatment. HDAC inhibitors (HDACIs) block angiogenesis, arrest cell growth, and lead to differentiation and apoptosis in tumor cells. In this article, a survey of published quantitative structure-activity relationships (QSARs) studies are presented and discussed in the hope of identifying the structural determinants for anticancer activity. Secondly a two-dimensional QSAR study was carried out on biological results derived from various types of HDACIs and from different assays using the C-QSAR program of Biobyte. The QSAR analysis presented here is an attempt to organize the knowledge on the HDACIs with the purpose of designing new chemical entities with enhanced inhibitory potencies and to study the mechanism of action of the compounds. This study revealed that lipophilicity is one of the most important determinants of activity. Additionally, steric factors such as the overall molar refractivity (CMR), molar volume (MgVol), the substituent's molar refractivity (MR) (linear or parabola), or the sterimol parameters B(1) and L are important. Electronic parameters indicated as σ(p), are found to be present only in one case.

A novel class I histone deacetylase inhibitor, I-7ab, induces apoptosis and arrests cell cycle progression in human colorectal cancer cells

“…Trichostatin A (TSA) was the first natural product that has been found to inhibit HDACs; however, its corresponding carboxylate, trichostatic acid, do not serve as a potent HDAC inhibitor [55]. This suggests that hydroxamate group is required for the activity of HDACis.…”

Targeting Selective Autophagy of Insoluble Protein Aggregates

“…Reviews describing structures and SARs for small molecule inhibitors of HDAC deacetylase enzymes are available [71,72]. The main indication for HDAC inhibitors is cancer [73,74] but other clinical indications are supported by preclinical evidence [75].…”

Integrating Structure and Ligand-Based Approaches for Modelling the Histone Deacetylase Inhibition Activity of Hydroxamic Acid Derivatives

“…In addition, various models were developed with very small dataset (<10 compounds) [18]. Consequently, the statistical significance and applicability of developed model become meaningless.…”

“…Pseudoreceptor methods, mainly 3D-QSAR techniques such as COMFA, COMSIA, and GOLPE, have been employed and showed higher performance in comparison with 2D-QSAR [14,18]. In this regard, structure-based methods, such as docking or molecular dynamics [22], are very useful to identify the "active conformation" of the ligands in the active sites of HDAC enzymes.…”