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Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia

Author

Listed:
  • Adriana E. Tron

    (AstraZeneca)

  • Matthew A. Belmonte

    (AstraZeneca
    LifeMine Therapeutics)

  • Ammar Adam

    (AstraZeneca
    Surface Oncology)

  • Brian M. Aquila

    (AstraZeneca
    Alkermes, Inc.)

  • Lawrence H. Boise

    (Emory University School of Medicine
    Winship Cancer Institute of Emory University)

  • Elisabetta Chiarparin

    (AstraZeneca)

  • Justin Cidado

    (AstraZeneca)

  • Kevin J. Embrey

    (AstraZeneca)

  • Eric Gangl

    (AstraZeneca)

  • Francis D. Gibbons

    (AstraZeneca)

  • Gareth P. Gregory

    (Monash University
    Peter MacCallum Cancer Centre)

  • David Hargreaves

    (AstraZeneca)

  • J. Adam Hendricks

    (AstraZeneca)

  • Jeffrey W. Johannes

    (AstraZeneca)

  • Ricky W. Johnstone

    (Peter MacCallum Cancer Centre
    University of Melbourne)

  • Steven L. Kazmirski

    (AstraZeneca
    Fulcrum Therapeutics)

  • Jason G. Kettle

    (AstraZeneca)

  • Michelle L. Lamb

    (AstraZeneca)

  • Shannon M. Matulis

    (Emory University School of Medicine
    Winship Cancer Institute of Emory University)

  • Ajay K. Nooka

    (Emory University School of Medicine
    Winship Cancer Institute of Emory University)

  • Martin J. Packer

    (AstraZeneca)

  • Bo Peng

    (AstraZeneca)

  • Philip B. Rawlins

    (AstraZeneca)

  • Daniel W. Robbins

    (AstraZeneca
    Nurix, Inc.)

  • Alwin G. Schuller

    (AstraZeneca)

  • Nancy Su

    (AstraZeneca)

  • Wenzhan Yang

    (AstraZeneca)

  • Qing Ye

    (AstraZeneca)

  • Xiaolan Zheng

    (AstraZeneca)

  • J. Paul Secrist

    (AstraZeneca
    LifeMine Therapeutics)

  • Edwin A. Clark

    (AstraZeneca)

  • David M. Wilson

    (AstraZeneca)

  • Stephen E. Fawell

    (AstraZeneca)

  • Alexander W. Hird

    (AstraZeneca)

Abstract

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).

Suggested Citation

  • Adriana E. Tron & Matthew A. Belmonte & Ammar Adam & Brian M. Aquila & Lawrence H. Boise & Elisabetta Chiarparin & Justin Cidado & Kevin J. Embrey & Eric Gangl & Francis D. Gibbons & Gareth P. Gregory, 2018. "Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07551-w
    DOI: 10.1038/s41467-018-07551-w
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    Cited by:

    1. Martina Troiani & Manuel Colucci & Mariantonietta D’Ambrosio & Ilaria Guccini & Emiliano Pasquini & Angelica Varesi & Aurora Valdata & Simone Mosole & Ajinkya Revandkar & Giuseppe Attanasio & Andrea R, 2022. "Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Andrea Lopez & Denis E. Reyna & Nadege Gitego & Felix Kopp & Hua Zhou & Miguel A. Miranda-Roman & Lars Ulrik Nordstrøm & Swathi-Rao Narayanagari & Ping Chi & Eduardo Vilar & Aristotelis Tsirigos & Evr, 2022. "Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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