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

  • Nat Commun. 2018 Dec 17;9(1):5341. doi: 10.1038/s41467-018-07551-w.
Adriana E Tron  1 ,  Matthew A Belmonte  1  2 ,  Ammar Adam  1  3 ,  Brian M Aquila  1  4 ,  Lawrence H Boise  5  6 ,  Elisabetta Chiarparin  7 ,  Justin Cidado  1 ,  Kevin J Embrey  8 ,  Eric Gangl  1 ,  Francis D Gibbons  1 ,  Gareth P Gregory  9  10 ,  David Hargreaves  8 ,  J Adam Hendricks  11 ,  Jeffrey W Johannes  1 ,  Ricky W Johnstone  10  12 ,  Steven L Kazmirski  11  13 ,  Jason G Kettle  7 ,  Michelle L Lamb  1 ,  Shannon M Matulis  5  6 ,  Ajay K Nooka  5  6 ,  Martin J Packer  14 ,  Bo Peng  1 ,  Philip B Rawlins  8 ,  Daniel W Robbins  1  15 ,  Alwin G Schuller  1 ,  Nancy Su  11 ,  Wenzhan Yang  16 ,  Qing Ye  1 ,  Xiaolan Zheng  1 ,  J Paul Secrist  1  2 ,  Edwin A Clark  1 ,  David M Wilson  7 ,  Stephen E Fawell  1 ,  Alexander W Hird  17
Affiliations
  • 1. Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.
  • 2. LifeMine Therapeutics, Cambridge, MA, USA.
  • 3. Surface Oncology, Cambridge, MA, USA.
  • 4. Alkermes, Inc., Waltham, MA, USA.
  • 5. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
  • 6. Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA.
  • 7. Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK.
  • 8. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, CB4 0WG, UK.
  • 9. School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, 3800, Australia.
  • 10. Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
  • 11. Discovery Sciences, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.
  • 12. The Sir Peter MacCallum Center, Department of Oncology, University of Melbourne, Parkville, VIC, 3000, Australia.
  • 13. Fulcrum Therapeutics, Cambridge, MA, USA.
  • 14. Oncology, IMED Biotech Unit, AstraZeneca, Alderley Park, SK10 4TG, UK.
  • 15. Nurix, Inc., San Francisco, CA, USA.
  • 16. Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA.
  • 17. Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, 02451, USA. [email protected].
PMID: 30559424 DOI: 10.1038/s41467-018-07551-w
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).

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