Journal of Medicinal Chemistry p. 11448 - 11468 (2020)
Update date:2022-08-03
Topics:
Lawson, Kenneth V.
Kalisiak, Jaroslaw
Lindsey, Erick A.
Newcomb, Eric T.
Leleti, Manmohan Reddy
Debien, Laurent
Rosen, Brandon R.
Miles, Dillon H.
Sharif, Ehesan U.
Jeffrey, Jenna L.
Tan, Joanne B. L.
Chen, Ada
Zhao, Sharon
Xu, Guifen
Fu, Lijuan
Jin, Lixia
Park, Tim W.
Berry, Wade
Moschütz, Susanne
Scaletti, Emma
Str?ter, Norbert
Walker, Nigel P.
Young, Stephen W.
Walters, Matthew J.
Schindler, Uli
Powers, Jay P.
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 (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.
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