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

Autor:	Li J; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Chen L; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Billedeau RJ; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Stanton TF; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Chiang JTP; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Lee CC; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Li W; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Steggerda S; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Emberley E; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Gross M; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Bhupathi D; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Che X; Wuxi AppTec, Shanghai 200131, China., Chen J; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Dang R; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Huang T; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Ma Y; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., MacKinnon A; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Makkouk A; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Marguier G; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Neou S; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Sotirovska N; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Spurlock S; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Zhang J; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Zhang W; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., van Zandt M; NEDP, Branford, Connecticut 06405, United States., Yuan L; NEDP, Branford, Connecticut 06405, United States., Savoy J; NEDP, Branford, Connecticut 06405, United States., Parlati F; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States., Sjogren EB; Calithera Biosciences, 343 Oyster Point Boulevard, South San Francisco, California 94080, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Jan 12; Vol. 66 (1), pp. 345-370. Date of Electronic Publication: 2022 Dec 18.
DOI:	10.1021/acs.jmedchem.2c01287
Abstrakt:	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.
Databáze:	MEDLINE
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