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Novel extracellular‐signal regulated kinase (ERK) substrate inhibitors mediate apoptotic signaling
Author(s) -
Boston Sarice R,
MacKerell Alexander D,
Shapiro Paul
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.680.1
Subject(s) - mapk/erk pathway , poly adp ribose polymerase , hela , phosphorylation , microbiology and biotechnology , apoptosis , kinase , signal transduction , protein kinase b , protein kinase a , chemistry , cancer cell , biology , biochemistry , cell , polymerase , cancer , enzyme , genetics
ERK proteins promote cancer cell proliferation and survival through substrate phosphorylation events. Thus, selective inhibition of substrates involved in these mechanisms provides promising targets for anti‐cancer therapies. Small molecules designed to interfere with ERK docking domains involved in substrate interactions were identified using computer‐aided drug design (CADD). A total of 184 compounds were tested in HeLa cells. Upon treatment, 35 compounds caused the induction of apoptotic signaling as measured by poly (ADP‐ribose) polymerase (PARP) cleavage. Importantly, these effects were not observed in non‐transformed cells. To evaluate the mechanism of apoptosis induction, ERK‐mediated Caspase‐9 phosphorylation, which prevents activation of the intrinsic apoptotic pathway, was inhibited by several of the active compounds. However, other active compounds inhibited Bim phosphorylation, a pro‐apoptotic protein whose ERK‐mediated phosphorylation results in proteosomal degradation. Moreover, induction of apoptotic signaling by the active compounds did not appear to be due to off target effects on Akt kinase, which also mediates pro‐survival mechanisms. Taken together, selective inhibition of ERK substrates promote apoptosis in HeLa cells, suggesting a novel approach in the development of new anti‐cancer therapeutics. (Supported by NIH Grant # CA120215‐01 to PS & CA120215‐02S to SB)