2. Academic Validation
  3. Discovery of novel ENPP1 inhibitors with benzotriazole core for cancer immunotherapy

Discovery of novel ENPP1 inhibitors with benzotriazole core for cancer immunotherapy

  • Eur J Med Chem. 2026 Apr 5:307:118666. doi: 10.1016/j.ejmech.2026.118666.
Junghwan Choi 1,  Sunwoo Lee 2,  Yong-Yea Park 2,  Jihun Kim 3,  Haein Kim 3,  Kyeongwon Moon 3,  Sunyoung Park 2,  Eun Kyung Yoo 2,  Chang Won Min 2,  Hyouk Woo Lee 2,  Hyun-Ju Park 3,  Pargat Singh 4,  Sungjoon Kim 5,  Chan Sun Park 6,  In Su Kim 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Txinno Bioscience Inc., Yongin, 16942, Republic of Korea.
  • 2 Txinno Bioscience Inc., Yongin, 16942, Republic of Korea.
  • 3 School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
  • 4 School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea. Electronic address: [email protected].
  • 5 Txinno Bioscience Inc., Yongin, 16942, Republic of Korea. Electronic address: [email protected].
  • 6 Txinno Bioscience Inc., Yongin, 16942, Republic of Korea. Electronic address: [email protected].
  • 7 School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea. Electronic address: [email protected].
PMID: 41687265 DOI: 10.1016/j.ejmech.2026.118666
Abstract

The cGAS-STING signaling pathway is an essential mechanism in the recruitment and activation of innate and adaptive immune cells to exert an antitumor response in Cancer Immunotherapy. cGAMP is a crucial immunotransmitter, which is potentially degraded by ENPP1, resulting in the deactivation of STING-mediated antitumor immune responses. We herein describe the design, synthesis, and biological evaluation of novel ENPP1 inhibitors containing a benzotriazole core and a sulfonimidamide Zn binder. Notably, compound 44a demonstrated potent and selective ENPP1 inhibition with an IC50 value of 13.1 nM and effectively activated the STING pathway in HCT116-Dual™ cells. Additionally, compound 44a exhibited a notable release of cytokines in THP-1 cell lines, thereby enhancing the innate immune response. The oral administration of compound 44a displayed remarkable antitumor efficacy in the MC38 syngeneic mouse model without notable toxicity. Therefore, compound 44a can be considered a promising candidate as a selective and orally bioavailable ENPP1 inhibitor.

Keywords

Benzotriazoles; Cancer; ENPP1; Immunotherapy; Sulfonimidamide; cGAMP.

Figures
Products