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K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

Author

Listed:
  • Jonathan M. Ostrem

    (Howard Hughes Medical Institute, University of California)

  • Ulf Peters

    (Howard Hughes Medical Institute, University of California)

  • Martin L. Sos

    (Howard Hughes Medical Institute, University of California)

  • James A. Wells

    (University of California)

  • Kevan M. Shokat

    (Howard Hughes Medical Institute, University of California)

Abstract

Small molecules are developed that irreversibly bind to the common G12C mutant of K-Ras but not the wild-type protein; crystallographic studies reveal the formation of an allosteric pocket that is not apparent in previous Ras studies, and the small molecules shift the affinity of K-Ras to favour GDP over GTP.

Suggested Citation

  • Jonathan M. Ostrem & Ulf Peters & Martin L. Sos & James A. Wells & Kevan M. Shokat, 2013. "K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions," Nature, Nature, vol. 503(7477), pages 548-551, November.
    • Handle: RePEc:nat:nature:v:503:y:2013:i:7477:d:10.1038_nature12796
    DOI: 10.1038/nature12796
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    Cited by:

    1. James Schiemer & Andrew Maxwell & Reto Horst & Shenping Liu & Daniel P. Uccello & Kris Borzilleri & Nisha Rajamohan & Matthew F. Brown & Matthew F. Calabrese, 2023. "A covalent BTK ternary complex compatible with targeted protein degradation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Hidenori Kitai & Philip H. Choi & Yu C. Yang & Jacob A. Boyer & Adele Whaley & Priya Pancholi & Claire Thant & Jason Reiter & Kevin Chen & Vladimir Markov & Hirokazu Taniguchi & Rui Yamaguchi & Hiromi, 2024. "Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Marie-Julie Nokin & Alessia Mira & Enrico Patrucco & Biagio Ricciuti & Sophie Cousin & Isabelle Soubeyran & Sonia San José & Serena Peirone & Livia Caizzi & Sandra Vietti Michelina & Aurelien Bourdon , 2024. "RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Arafath K. Najumudeen & Sigrid K. Fey & Laura M. Millett & Catriona A. Ford & Kathryn Gilroy & Nuray Gunduz & Rachel A. Ridgway & Eve Anderson & Douglas Strathdee & William Clark & Colin Nixon & Jenni, 2024. "KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Katharine M. Wright & Sarah R. DiNapoli & Michelle S. Miller & P. Aitana Azurmendi & Xiaowei Zhao & Zhiheng Yu & Mayukh Chakrabarti & WuXian Shi & Jacqueline Douglass & Michael S. Hwang & Emily Han-Ch, 2023. "Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Kai-Bo Wang & Yushuang Liu & Jinzhu Li & Chengmei Xiao & Yingying Wang & Wei Gu & Yipu Li & Yuan-Zheng Xia & Tingdong Yan & Ming-Hua Yang & Ling-Yi Kong, 2022. "Structural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Johanna Lilja & Jasmin Kaivola & James R. W. Conway & Joni Vuorio & Hanna Parkkola & Pekka Roivas & Michal Dibus & Megan R. Chastney & Taru Varila & Guillaume Jacquemet & Emilia Peuhu & Emily Wang & U, 2024. "SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    8. Kaja Kostyrko & Marta Román & Alex G. Lee & David R. Simpson & Phuong T. Dinh & Stanley G. Leung & Kieren D. Marini & Marcus R. Kelly & Joshua Broyde & Andrea Califano & Peter K. Jackson & E. Alejandr, 2023. "UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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