Discovery of a Series of Potent, Selective, and Orally Bioavailable Nucleoside Inhibitors of CD73 That Demonstrates In Vivo Antitumor Activity

  • J Med Chem. 2022 Dec 18. doi: 10.1021/acs.jmedchem.2c01287.
Jim Li  1 Lijing Chen  1 Roland J Billedeau  1 Timothy F Stanton  1 John T P Chiang  1 Clarissa C Lee  1 Weiqun Li  1 Susanne Steggerda  1 Ethan Emberley  1 Matthew Gross  1 Deepthi Bhupathi  1 Xiaoying Che  2 Jason Chen  1 Rosalyn Dang  1 Tony Huang  1 Yong Ma  1 Andrew MacKinnon  1 Amani Makkouk  1 Gisele Marguier  1 Silinda Neou  1 Natalija Sotirovska  1 Sandra Spurlock  1 Jing Zhang  1 Winter Zhang  1 Michael van Zandt  3 Lin Yuan  3 Jennifer Savoy  3 Francesco Parlati  1 Eric B Sjogren  1
Affiliations
  • 1. Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States.
  • 2. Wuxi AppTec, Shanghai 200131, China.
  • 3. NEDP, Branford, Connecticut 06405, United States.
Abstract

CD73 (ecto-5'-nucleotidase) has emerged as an attractive target for Cancer Immunotherapy of many cancers. CD73 catalyzes the hydrolysis of adenosine monophosphate (AMP) into highly immunosuppressive adenosine that plays a critical role in tumor progression. Herein, we report our efforts in developing orally bioavailable and highly potent small-molecule CD73 inhibitors from the reported hit molecule 2 to lead molecule 20 and then finally to compound 49. Compound 49 was able to reverse AMP-mediated suppression of CD8+ T cells and completely inhibited CD73 activity in serum samples from various Cancer patients. In preclinical in vivo studies, orally administered 49 showed a robust dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship that correlated with efficacy. Compound 49 also demonstrated the expected immune-mediated antitumor mechanism of action and was efficacious upon oral administration not only as a single agent but also in combination with either chemotherapeutics or checkpoint inhibitor in the mouse tumor model.

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