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

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

doi:10.1021/jm401291q

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

J Med Chem. 2013 Dec 12;56(23):9664-72. doi: 10.1021/jm401291q. Epub 2013 Nov 22.

Authors

Miriam Schöpel¹, 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

Affiliation

¹ Faculty of Chemistry and Biochemistry, Ruhr University of Bochum , Universitätsstraße 150, D-44780 Bochum, Germany.

PMID: 24266771
DOI: 10.1021/jm401291q

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzhydryl Compounds / chemistry
Benzhydryl Compounds / 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
Monomeric GTP-Binding Proteins / metabolism*
Neuropeptides / antagonists & inhibitors
Neuropeptides / metabolism*
Nuclear Magnetic Resonance, Biomolecular
Phenols / chemistry
Phenols / pharmacology*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins p21(ras)
Ras Homolog Enriched in Brain Protein
SOS Response, Genetics / drug effects
ras Proteins / metabolism*

Substances

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