2. Academic Validation
  3. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia

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

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. alexander.hird@astrazeneca.com.
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).

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z