Bisphenol A binds to Ras proteins and competes with guanine nucleotide exchange: implications for GTPase-selective antagonists.

Abstract

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.

• Authors: Miriam Schöpel, Katharina F G Jockers, Peter M Düppe, Jasmin Autzen, Veena N Potheraveedu, Semra Ince, King Tuo Yip, Rolf Heumann, Christian Herrmann, Jürgen Scherkenbeck, Raphael Stoll
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 23 Pg. 9664-72 (Dec 12 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 24266771 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzhydryl Compounds
• Biphenyl Compounds
• Guanine Nucleotide Exchange Factors
• KRAS protein, human
• Neuropeptides
• Phenols
• Proto-Oncogene Proteins
• RHEB protein, human
• Ras Homolog Enriched in Brain Protein
• Guanosine Diphosphate
• GTP Phosphohydrolases
• Monomeric GTP-Binding Proteins
• Proto-Oncogene Proteins p21(ras)
• ras Proteins
• bisphenol A
• 4,4'-dihydroxybiphenyl

Topics

• Benzhydryl Compounds (chemistry, pharmacology)
• Biphenyl Compounds (pharmacology)
• GTP Phosphohydrolases (antagonists & inhibitors)
• Guanine Nucleotide Exchange Factors (metabolism)
• Guanosine Diphosphate (metabolism)
• HeLa Cells
• Humans
• Models, Molecular
• Monomeric GTP-Binding Proteins (antagonists & inhibitors, metabolism)
• Neuropeptides (antagonists & inhibitors, metabolism)
• Nuclear Magnetic Resonance, Biomolecular
• Phenols (chemistry, pharmacology)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins p21(ras)
• Ras Homolog Enriched in Brain Protein
• SOS Response, Genetics (drug effects)
• ras Proteins (metabolism)