Entinostat and novel analogs: preclinical evidence for anti-proliferative activity in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) has low overall survival, underscoring the need for the development of novel approaches. Present study aimed to investigate anti-proliferative effects of entinostat and its newly synthesized analogs on ATLL cells. Computational analyses were conducted to identify the potential molecular targets of entinostat, and construct a protein-protein interaction network. Then, enrichment analyses were performed, and the expression of CDK4 was assessed in MT-2 cells. Molecular docking and dynamics simulations were carried out to predict the interactions of entinostat and its novel analogs with target proteins. For in vitro studies, at first quinoline-based benzamide derivatives were synthesized. Then, MT-2 and normal cells were treated and their proliferation was evaluated by alamarBlue assay. Finally, flow cytometry was performed, and the expression of candidate genes was assessed by real-time PCR. Exploring potential targets of entinostat and pathogenic targets of ATLL revealed 51 overlapping molecules including CDK4. Volcano plot revealed over expression of CDK4 in MT-2 cells. Favorable and stable binding of entinostat and its analogs with the activation loop of CDK4 and the CDK-binding site of cyclin D1 was confirmed. Experimental studies revealed anti-proliferative effects of entinostat and analogs on MT-2 cells, confirmed by flow cytometry analysis and alterations in the expression of BAX, CCND1, and BCL-2. Present findings pave the way for the development of new drugs against ATLL, and provide evidence that justifies further preclinical evaluations of entinostat and its novel analogs.