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
  • 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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