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Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo

Author

Listed:
  • Tamer S. Kaoud

    (The University of Texas at Austin
    Minia University)

  • William H. Johnson

    (The University of Texas at Austin)

  • Nancy D. Ebelt

    (The University of Texas at Austin)

  • Andrea Piserchio

    (The City College of New York)

  • Diana Zamora-Olivares

    (The University of Texas at Austin)

  • Sabrina X. Ravenstein

    (The University of Texas at Austin)

  • Jacey R. Pridgen

    (The University of Texas at Austin)

  • Ramakrishna Edupuganti

    (The University of Texas at Austin)

  • Rachel Sammons

    (The University of Texas at Austin)

  • Micael Cano

    (The University of Texas at Austin)

  • Mangalika Warthaka

    (The University of Texas at Austin)

  • Matthew Harger

    (The University of Texas at Austin)

  • Clint D. J. Tavares

    (Harvard Medical School)

  • Jihyun Park

    (The University of Texas MD Anderson Cancer Center)

  • Mohamed F. Radwan

    (King Abdulaziz University)

  • Pengyu Ren

    (The University of Texas at Austin)

  • Eric V. Anslyn

    (The University of Texas at Austin)

  • Kenneth Y. Tsai

    (Moffitt Cancer Center)

  • Ranajeet Ghose

    (The City College of New York
    The Graduate Center of the City University of New York)

  • Kevin N. Dalby

    (The University of Texas at Austin)

Abstract

Recently, the targeting of ERK with ATP-competitive inhibitors has emerged as a potential clinical strategy to overcome acquired resistance to BRAF and MEK inhibitor combination therapies. In this study, we investigate an alternative strategy of targeting the D-recruitment site (DRS) of ERK. The DRS is a conserved region that lies distal to the active site and mediates ERK–protein interactions. We demonstrate that the small molecule BI-78D3 binds to the DRS of ERK2 and forms a covalent adduct with a conserved cysteine residue (C159) within the pocket and disrupts signaling in vivo. BI-78D3 does not covalently modify p38MAPK, JNK or ERK5. BI-78D3 promotes apoptosis in BRAF inhibitor-naive and resistant melanoma cells containing a BRAF V600E mutation. These studies provide the basis for designing modulators of protein–protein interactions involving ERK, with the potential to impact ERK signaling dynamics and to induce cell cycle arrest and apoptosis in ERK-dependent cancers.

Suggested Citation

  • Tamer S. Kaoud & William H. Johnson & Nancy D. Ebelt & Andrea Piserchio & Diana Zamora-Olivares & Sabrina X. Ravenstein & Jacey R. Pridgen & Ramakrishna Edupuganti & Rachel Sammons & Micael Cano & Man, 2019. "Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12996-8
    DOI: 10.1038/s41467-019-12996-8
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    Cited by:

    1. Ádám Levente Póti & Dániel Bálint & Anita Alexa & Péter Sok & Kristóf Ozsváth & Krisztián Albert & Gábor Turczel & Sarolt Magyari & Orsolya Ember & Kinga Papp & Sándor Balázs Király & Tímea Imre & Kri, 2024. "Targeting a key protein-protein interaction surface on mitogen-activated protein kinases by a precision-guided warhead scaffold," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. François Virard & Stéphane Giraud & Mélanie Bonnet & Léa Magadoux & Laetitia Martin & Thuy Ha Pham & Najwa Skafi & Sophie Deneuve & Rita Frem & Bruno O. Villoutreix & Nawal Hajj Sleiman & Jonathan Reb, 2024. "Targeting ERK-MYD88 interaction leads to ERK dysregulation and immunogenic cancer cell death," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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