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ID: ALA4665688
Journal: J Med Chem
Title: Discovery of AB680: A Potent and Selective Inhibitor of CD73.
Authors: Lawson KV,Kalisiak J,Lindsey EA,Newcomb ET,Leleti MR,Debien L,Rosen BR,Miles DH,Sharif EU,Jeffrey JL,Tan JBL,Chen A,Zhao S,Xu G,Fu L,Jin L,Park TW,Berry W,Moschütz S,Scaletti E,Sträter N,Walker NP,Young SW,Walters MJ,Schindler U,Powers JP
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 → AMP) and CD73 (AMP → 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 (K = 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.
CiteXplore: 32614585