Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs
Nature Chemical Biology. 2025
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Sadagopan A, Carson M, Zamurs EJ, Garaffo N, Chang HJ, Schreiber SL, Meyerson M, Gibson WJ
We demonstrate a targeted approach to selectively eliminate TP53 mutant cancer cells by exploiting the increased abundance of mutant p53 protein, using an induced proximity strategy to concentrate a toxic molecule specifically within these cells.
We engineered bifunctional compounds that induce nuclear import of cytosolic proteins by using nuclear-localized BRD4 as a carrier. This paper helped to seed the field of “Targeted Protein Relocalization” and the sorts of compounds in it may one day be useful for treating diseases ranging from cancer to neurodegenerative disease.
We demonstrate that bifunctional small molecules targeting p300/CBP can be recruited to tagged transcription factors to produce context-dependent transcriptional outcomes, toggling between potent transactivation and repression, and reveal at least three mechanistically distinct consequences when applied to the oncogenic fusion proteins.
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Gibson WJ, Ruan DT, Paulson VA, Barletta JA, Hanna GJ, Kraft S, Calles A, Nehs MA, Moore FD Jr, Taylor-Weiner A, Wala JA, Zack TI, Lee TC, Fennessy FM, Alexander EK, Thomas T, Janne PA, Garraway LA, Carter SL, Beroukhim R, Lorch JH, Van Allen EM.Clin Cancer Res. 2017 May 1;23(9):2367-2373.
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The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis.
Gibson WJ, Hoivik EA, Halle MK, Taylor-Weiner A, Cherniack AD, Berg A, Holst F, Zack TI, Werner HM, Staby KM, Rosenberg M, Stefansson IM, Kusonmano K, Chevalier A, Mauland KK, Trovik J, Krakstad C, Giannakis M, Hodis E, Woie K, Bjorge L, Vintermyr OK, Wala JA, Lawrence MS, Getz G, Carter SL, Beroukhim R, Salvesen HB.Nat Genet. 2016 Aug;48
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