guanosine-diphosphate and 4-4--dihydroxybiphenyl

We show for the first time that bisphenol A (10) has the capacity to interact directly with K-Ras and that Rheb weakly binds to bisphenol A (10) and 4,4'-biphenol derivatives. We have characterized these interactions at atomic resolution suggesting that these compounds sterically interfere with the Sos-mediated nucleotide exchange in H- and K-Ras. We show that 4,4'-biphenol (5) selectively inhibits Rheb signaling and induces cell death suggesting that this compound might be a novel candidate for treatment of tuberous sclerosis-mediated tumor growth. Our results propose a new mode of action for bisphenol A (10) that advocates a reduced exposure to this compound in our environment. Our data may lay the foundation for the future design of GTPase-selective antagonists with higher affinity to benefit of the treatment of cancer because K-Ras inhibition is regarded to be a promising strategy with a potential therapeutic window for targeting Sos in Ras-driven tumors.

Topics: Benzhydryl Compounds; Biphenyl Compounds; GTP Phosphohydrolases; Guanine Nucleotide Exchange Factors; Guanosine Diphosphate; HeLa Cells; Humans; Models, Molecular; Monomeric GTP-Binding Proteins; Neuropeptides; Nuclear Magnetic Resonance, Biomolecular; Phenols; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Ras Homolog Enriched in Brain Protein; ras Proteins; SOS Response, Genetics