Cho, Yeonguk KANG MISO Ji suhyun Jeong, Hee Jin Cheong Jaeeun Oh, Do Hee Park, Sunyoung Park, Yong-Yea Choi, Junghwan Kim, Sungjoon Kim, Nam-Jung Lee, Duck-Hyung Park, Chan Sun Han, Seojung Lee, Sanghee Choi, Junwon 2024-01-12T06:32:46Z 2024-01-12T06:32:46Z 2023-11-16 2023-11 0022-2623 https://pubs.kist.re.kr/handle/201004/79765 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. English American Chemical Society Discovery of Orally Bioavailable Phthalazinone Analogues as an ENPP1 Inhibitor for STING-Mediated Cancer Immunotherapy Article 10.1021/acs.jmedchem.3c01061 1 Journal of Medicinal Chemistry, v.66, no.22, pp.15141 - 15170 Journal of Medicinal Chemistry 66 22 15141 15170 N scie scopus 001140896700001 Chemistry, Medicinal Pharmacology & Pharmacy Article CYCLIC GMP-AMP DERIVATIVES DESIGN