Journal of medicinal and pharmaceutical chemistry 2013-12-12

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

文献索引：J. Med. Chem. 56(23) , 9664-72, (2013)

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摘要

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.