posted on 2023-11-15, 03:20authored byYeonguk Cho, Miso Kang, Su Hyun Ji, Hee Jin Jeong, Jae Eun Jung, Do Hee Oh, Sunyoung Park, Yong-Yea Park, Junghwan Choi, Sungjoon Kim, Nam-Jung Kim, Duck-Hyung Lee, Chan Sun Park, Seo-Jung Han, Sanghee Lee, Junwon Choi
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.