A1 Refereed original research article in a scientific journal
X-Ray Co-Crystal Structure Guides the Way to Subnanomolar Competitive Ecto-5 '-Nucleotidase (CD73) Inhibitors for Cancer Immunotherapy
Authors: Sanjay Bhattarai, Jan Pippel, Anne Meyer, Marianne Freundlieb, Constanze Schmies, Aliaa Abdelrahman, Amelie Fiene, Sang-Yong Lee, Herbert Zimmermann, Ali El-Tayeb, Gennady G. Yegutkin, Norbert Sträter, Christa E. Muller
Publisher: WILEY
Publication year: 2019
Journal: Advanced therapeutics
Journal name in source: ADVANCED THERAPEUTICS
Journal acronym: ADV THER-GERMANY
Article number: UNSP 1900075
Volume: 2
Issue: 10
Number of pages: 8
eISSN: 2366-3987
DOI: https://doi.org/10.1002/adtp.201900075
Web address : https://onlinelibrary.wiley.com/doi/full/10.1002/adtp.201900075
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/45222165
Ecto-5'-nucleotidase (CD73, EC 3.1.3.5) catalyzes the extracellular hydrolysis of AMP yielding adenosine, which induces immunosuppression, angiogenesis, metastasis, and proliferation of cancer cells. CD73 inhibition is therefore proposed as a novel strategy for cancer (immuno)therapy, and CD73 antibodies are currently undergoing clinical trials. Despite considerable efforts, the development of small molecule CD73 inhibitors has met with limited success. To develop a suitable drug candidate, a high resolution (2.05 degrees A) co-crystal structure of the CD73 inhibitor PSB-12379, a nucleotide analogue, in complex with human CD73 is determined. This allows the rational design and development of a novel inhibitor (PSB-12489) with subnanomolar inhibitory potency toward human and rat CD73, high selectivity, as well as high metabolic stability. A co-crystal structure of PSB-12489 with CD73 (1.85 degrees A) reveals the interactions responsible for increased potency. PSB-12489 is the most potent CD73 inhibitor to date representing a powerful tool compound and novel lead structure.
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