1. Academic Validation
  2. Discovery of a Series of Potent, Selective, and Orally Bioavailable Nucleoside Inhibitors of CD73 That Demonstrates In Vivo Antitumor Activity

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

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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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-152074
    CD73抑制剂