LC-0882 targets PAK4 and inhibits PAK4-related signaling pathways to suppress the proliferation and invasion of gastric cancer cells.

Gastric cancer is the most common malignant tumor and globally the third leading cause of cancer-related deaths. Therefore, there exists an urgent need to identify new effective gastric cancer treatments. Given the important roles in tumorigenesis and progression, p21-activated kinase 4 (PAK4) has been regarded as an attractive high-value druggable target. In this study, we examined the effects and molecular mechanisms of action of the small molecular compound LC-0882 on gastric cancer cells in vitro. LC-0882 was found to significantly inhibit the proliferation of human gastric cancer cells by repressing phospho-PAK4/cyclin D1 and CDK4/6 expression. In addition, LC-0882 was found to attenuate cell invasion by blocking the PAK4/LIMK1/cofilin signaling pathway. Finally, analysis of immunofluorescence revealed that LC-0882 exposure decreased filopodia formation and induced cell elongation in BGC823 and SGC7901 gastric cancer cells. These findings suggest that targeting PAK4 with the novel compound LC-0882 may provide a new chemotherapeutic approach in gastric cancer treatment.

Molecular recognition of CYP26A1 binding pockets and structure-activity relationship studies for design of potent and selective retinoic acid metabolism blocking agents.

All-trans-retinoic acid (ATRA), the biologically most active metabolite of vitamin A, plays a major role in the regulation of cellular differentiation and proliferation, and it is also an important pharmacological agent particularly used in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. However, ATRA is very easy to be metabolized into 4-hydroxyl-RA in vivo by CYP26A1, an inducible cytochrome P450 enzyme, eventually into more polar metabolites. Therefore, it is vital to develop specific retinoic acid metabolism blocking agents (RAMBAs) to inhibit the metabolic enzyme CYP26A1 in the treatment of relevant diseases aforementioned. In this study, CYP26A1 and its interactions with retinoic acid-competitive metabolism blocking agents were investigated by a combined ligand- and structure-based approach. First, since the crystal structure of CYP26A1 protein has not been determined, we constructed the 3D structure of CYP26A1 using homology modeling. In order to achieve a deeper insight into the mode of action of RAMBAs in the active site, the molecular superimposition model and the common feature pharmacophore model were constructed, and molecular docking was performed. The molecular superimposition model is composed of three features: the main chain groups, side chain groups, and azole groups. The common feature pharmacophore model consists of five chemical features: four hydrophobic groups and one hydrogen acceptor (HHHHA). The results of molecular docking show that the characteristic groups of RAMBAs were mapped into three different active pockets, respectively. A structure-activity relationship (SAR) was obtained by a combination of the molecular superimposition and docking results with the pharmacophore model. This study gives more insight into the interaction model inside the CYP26A1 active site and provides guidance for the design of more potent and possibly more selective RAMBAs.