Targeting sirt and its pathway for therapeutic intervention of Cancer drug design and biological evaluation

Abstract

Cancer is a complicated disease so is its treatment. For the past many decades, research has been newlineprogressing, yet tip of the iceberg are only known about its etiology. The understanding about newlinethe characteristics and the hallmarks of cancer have been increasing day by day. Similarly, newlineresearch on various proteins and their role in cancer complication has been the primary focus of newlineresearch. Discovering small molecule modulators of these proteins (enzymes) might fill the large newlinegap in cancer therapeutics. Further, it also might help in understanding the mechanistic role in newlinevarious pathways. Human SIRT1, a homologous protein of yeast sir2 enzyme, deacetylates newlinehistone and non histone proteins. It modulates the epigenetic regulation of various genes newlineinvolved in cancer, which include various transcription factors and DNA repair enzymes. newlineFurther, it was known to be overexpressed in many cancer conditions and partial suppression of newlineSIRT1 activity had reduced cancer symptoms. SIRT1 function is modulated by NAD+ newlinelevels in newlinethe cell, which acts as a co-substrate for SIRT1 activity. NAMPT is a rate limiting enzyme newlineinvolved in the synthesis of NAD+ and interestingly, it was also found overexpressed in many newlinecancer conditions. Hence the prime objective of our study was to design small molecule newlineinhibitors against SIRT1 and NAMPT to treat cancer conditions. Thus, we employed both newlinestructure and ligand based drug designing strategies to discover small molecule inhibitors against newlineboth the proteins (SIRT1 and NAMPT). newlineIn the present study, a diverse and novel set of molecules as SIRT1 and NAMPT inhibitors were newlineinitially identified and were further experimentally evaluated employing in-vitro enzymatic newlinev newlineassays. Potent molecules where further studied their anticancer activates in various cancer cell newlinelines and molecules showing best activity were further evaluated their activity in benign prostatehyperplasia animal model. newlineAmong all the identified SIRT1 inhibitors, Lead17 was found to be most potent with IC50 of4.34 and#956;M and GIC50 of 360 nM