Inverse in silico–in vitro fishing of unexpected paroxetine kinase targets from tumor druggable kinome

Paroxetine—Overview of the Molecular Mechanisms of Action

“…Paroxetine can influence a variety of cancers, including brain tumor [ 139 ], colon cancer [ 140 ] and breast cancer [ 141 ] by blocking some protein kinase signaling pathways involved in tumorigenesis [ 142 ].…”

“…Many studies have established that this is due to the structural similarities (size, shape, physicochemical properties, Figure 6 ) of paroxetine with many known kinase inhibitors. Consequently, it is not surprising that paroxetine is very compatible with the kinase active site [ 142 ]. A good example of paroxetine’s similarity are sunitinib, approved a multitargeted tyrosine kinase inhibitor (KIT inhibitor) [ 143 , 144 ] and tofacitinib (approved Janus kinase inhibitor (JAK inhibitor)) [ 145 ] ( Figure 6 ).…”

“…Tyrosine kinase proteins are a class of proteins with tyrosine kinase activity that catalyzes the transfer of phosphate groups to ATP to the residues of tyrosine of many important proteins, forming protein phosphorylation and then transmitting a signal regulating cell growth, differentiation, death and a number of physiological and biochemical processes [ 151 ]. Paroxetine can interact with these kinases in two so-called binding modes: class I and class II [ 142 ]. Five kinases in the C-Src ABL, SRC, KIT, MET and FYN family were identified as targets for paroxetine kinase, which can be inhibited strongly or moderately at IC 50 values at the nanomolar or micromolar level.…”

“…While in class II, the same molecular fragment of paroxetine adopts the opposite binding mode. It seems noteworthy that paroxetine class I binding mode shows much higher inhibition potential than that of class II [ 142 ].…”

Пароксетин – Репозиционирование – Новые Грани

“…В 2020 г. было опубликовано исследование о том, что пароксетин, селективный ингибитор обратного захвата серотонина, оказывает значительное подавляющее действие на опухоли человека, неожиданно воздействуя на различные киназные пути, участвующие в онкогенезе. Анализ жизнеспособности клеток продемонстрировал, что пароксетин обладает сильной цитотоксичностью по отношению к пулам опухолевых клеток человека [12].…”