Discovery of AB680: A Potent and Selective Inhibitor of CD73.
J Med Chem
; 63(20): 11448-11468, 2020 10 22.
Article
em En
| MEDLINE
| ID: mdl-32614585
ABSTRACT
Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP â AMP) and CD73 (AMP â ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure-activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (Ki = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clinical trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
5'-Nucleotidase
/
Bibliotecas de Moléculas Pequenas
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Descoberta de Drogas
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2020
Tipo de documento:
Article