Discovery of Orally Bioavailable Phthalazinone Analogues as an ENPP1 Inhibitor for STING-Mediated Cancer Immunotherapy

A lack of the T cell-inflamed tumor microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs). Activation of stimulator of interferon genes (STING)-mediated innate immunity has emerged as a novel therapeutic approach in cancer therapy. 2',3'-Cyclic GMP-AMP (cGAMP) is a na...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2023-11, Vol.66 (22), p.15141-15170
Main Authors: Cho, Yeonguk, Kang, Miso, Ji, Su Hyun, Jeong, Hee Jin, Jung, Jae Eun, Oh, Do Hee, Park, Sunyoung, Park, Yong-Yea, Choi, Junghwan, Kim, Sungjoon, Kim, Nam-Jung, Lee, Duck-Hyung, Park, Chan Sun, Han, Seo-Jung, Lee, Sanghee, Choi, Junwon
Format: Article
Language:English
Subjects:
Humans
Immunotherapy
Neoplasms - therapy
Phosphoric Diester Hydrolases - metabolism
Pyrophosphatases
Tumor Microenvironment
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Summary:A lack of the T cell-inflamed tumor microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs). Activation of stimulator of interferon genes (STING)-mediated innate immunity has emerged as a novel therapeutic approach in cancer therapy. 2',3'-Cyclic GMP-AMP (cGAMP) is a natural STING agonist; however, cGAMP is subjected to endogenous degradation by ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1). To improve the ICI response rate, we developed , a novel ENPP1 inhibitor with phthalazin-1(2 )-one as the core scaffold. inhibited the cGAMP hydrolysis by ENPP1 in vitro (IC = 68 nM) and enhanced the STING-mediated type I interferon response in both immune and tumor cells. demonstrated excellent metabolic stability and bioavailability ( = 65%). Orally administered promoted tumor growth inhibition in a CT26 syngeneic model and increased the anti-PD-L1 response. Furthermore, -induced immunological memory prevented the tumor relapse against tumor rechallenge, suggesting the promising therapeutic potential of .
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c01061