Induction of apoptosis by novel substrate selective extracellular signal‐regulated kinase (ERK) inhibitors

Abstract

The ERK proteins are potent mediators of cell proliferation and survival. Unregulated activation of the ERK proteins plays a role in the progression of a variety of cancers. Thus, targeted inhibition of ERK's function in promoting cell proliferation and survival is viewed as a promising approach for anti‐cancer therapy. Using in silico modeling, we have recently developed small molecular weight compounds that target ERK domains involved in specific substrate interactions. Compounds designed to target the common docking (CD) domain on ERK2 were tested for their ability to block anti‐apoptotic mechanisms involving ERK phosphorylation of p90RSK‐1, which promotes cell survival by phosphorylating and inactivating the pro‐apoptotic protein BAD. HeLa cells treated with 50 μM of one compound (termed 76) caused induction of apoptotic signaling pathways as measured by cleavage of poly (ADP‐ribose) polymerase (PARP), which was observed within 3 hours. PARP cleavage induced by 76 required activation of the intrinsic apoptotic pathway, specifically caspase 9 and caspase 3. Compound 76 inhibited p90RSK‐1 phosphorylation of BAD in a manner that correlates with caspase activation. Furthermore, inhibition of BAD phosphorylation in the presence of compound 76 was not due to off‐target effects on other pro‐survival pathways. These findings suggest that substrate selective inhibition of ERK signaling promotes apoptosis in transformed cells, illustrating a novel approach to the development of anti‐cancer therapies. (Supported by NIH CA120215)