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

Autor: Nancy Su, Brian Aquila, Gareth P. Gregory, Stephen Fawell, J. Adam Hendricks, Ammar Adam, Lawrence H. Boise, Jeffrey W. Johannes, Kevin J. Embrey, Edwin Clark, Philip B. Rawlins, Justin Cidado, Francis D. Gibbons, Ricky W. Johnstone, Qing Ye, Elisabetta Chiarparin, Steven L. Kazmirski, Michelle Lamb, J. Paul Secrist, Wenzhan Yang, Alexander Hird, Daniel W. Robbins, Adriana E. Tron, Alwin Schuller, Martin J. Packer, David J. Hargreaves, Xiaolan Zheng, Matthew A. Belmonte, Eric Gangl, Ajay K. Nooka, Shannon M. Matulis, Jason Grant Kettle, Bo Peng, David Matthew Wilson
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Myeloid
General Physics and Astronomy
Apoptosis
Mice
SCID
medicine.disease_cause
Crystallography
X-Ray
Bortezomib
chemistry.chemical_compound
Mice
0302 clinical medicine
immune system diseases
hemic and lymphatic diseases
lcsh:Science
Multiple myeloma
Sulfonamides
Multidisciplinary
Myeloid leukemia
Leukemia
Leukemia
Myeloid
Acute
medicine.anatomical_structure
030220 oncology & carcinogenesis
Multiple Myeloma
medicine.drug
Science
Antineoplastic Agents
General Biochemistry
Genetics and Molecular Biology
Article
03 medical and health sciences
Rats
Nude
Cell Line
Tumor
medicine
Animals
Humans
neoplasms
Venetoclax
business.industry
General Chemistry
medicine.disease
Bridged Bicyclo Compounds
Heterocyclic
Xenograft Model Antitumor Assays
Rats
Mice
Inbred C57BL
030104 developmental biology
chemistry
Cancer cell
Cancer research
Myeloid Cell Leukemia Sequence 1 Protein
lcsh:Q
Carcinogenesis
business
Zdroj: Nature Communications, Vol 9, Iss 1, Pp 1-14 (2018)
Nature Communications
ISSN: 2041-1723
DOI: 10.1038/s41467-018-07551-w
Popis: 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).
High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.
Databáze: OpenAIRE
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