2. Academic Validation
  3. Discovery of Orally Bioavailable Phthalazinone Analogues as an ENPP1 Inhibitor for STING-Mediated Cancer Immunotherapy

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

  • J Med Chem. 2023 Nov 23;66(22):15141-15170. doi: 10.1021/acs.jmedchem.3c01061.
Yeonguk Cho 1,  Miso Kang 2 3,  Su Hyun Ji 4 5,  Hee Jin Jeong 4,  Jae Eun Jung 4,  Do Hee Oh 4,  Sunyoung Park 6,  Yong-Yea Park 6,  Junghwan Choi 6,  Sungjoon Kim 6,  Nam-Jung Kim 2,  Duck-Hyung Lee 5,  Chan Sun Park 6,  Seo-Jung Han 4 7,  Sanghee Lee 3 8,  Junwon Choi 1
Affiliations

Affiliations

  • 1 Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea.
  • 2 Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 3 Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
  • 4 Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
  • 5 Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea.
  • 6 Txinno Bioscience Inc., Yongin 16942, Republic of Korea.
  • 7 Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea.
  • 8 Department for HY-KIST Bio-convergence, Hanyang University, Seoul 04763, Republic of Korea.
PMID: 37963811 DOI: 10.1021/acs.jmedchem.3c01061
Abstract

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 29f, a novel ENPP1 inhibitor with phthalazin-1(2H)-one as the core scaffold. 29f inhibited the cGAMP hydrolysis by ENPP1 in vitro (IC50 = 68 nM) and enhanced the STING-mediated type I interferon response in both immune and tumor cells. 29f demonstrated excellent metabolic stability and bioavailability (F = 65%). Orally administered 29f promoted tumor growth inhibition in a CT26 syngeneic model and increased the anti-PD-L1 response. Furthermore, 29f-induced immunological memory prevented the tumor relapse against tumor rechallenge, suggesting the promising therapeutic potential of 29f.

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