2. Academic Validation
  3. Discovery of (4-Phenyl-cyclohexyl)acetate-Derived Tyrosylprotein Sulfotransferase 2 (TPST2) Inhibitors with Potent Anti-Tumor Activity for Immuno-Oncology Applications

Discovery of (4-Phenyl-cyclohexyl)acetate-Derived Tyrosylprotein Sulfotransferase 2 (TPST2) Inhibitors with Potent Anti-Tumor Activity for Immuno-Oncology Applications

  • J Med Chem. 2025 Nov 13;68(21):22401-22427. doi: 10.1021/acs.jmedchem.5c01391.
Soo Bin Park 1,  Hyun Kim 2,  Yumi Oh 3,  Minwoo Jin 1 4,  Myeonggil Jeon 1,  Yunjae Kim 2,  Taein Park 4 5,  Jihyun Kim 1,  Beomki Cho 2,  Chaemin Noh 1 4,  Jihyeok Cho 1,  Je-Heon Lee 1,  Chanyeong Jeong 2,  Ji-Woo Mok 1,  Soo Hyun Eom 1 4 5,  Sung-Yup Cho 3 6 7,  Hansoo Park 2 8,  Yong-Chul Kim 1 9
Affiliations

Affiliations

  • 1 Department of Life Sciences, Gwangju Institute of Science and Technology (GIST), 123, Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Republic of Korea.
  • 2 Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), 123, Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Republic of Korea.
  • 3 Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, 1, Gwanak-ro, Gwanak-gu, Seoul 03080, Republic of Korea.
  • 4 Steitz Center for Structural Biology, Gwangju Institute of Science and Technology (GIST), 123, Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Republic of Korea.
  • 5 Department of Chemistry, Gwangju Institute of Science and Technology (GIST), 123, Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Republic of Korea.
  • 6 Department of Biomedical Sciences, Seoul National University College of Medicine, 1, Gwanak-ro, Gwanak-gu, Seoul 03080, Republic of Korea.
  • 7 Cancer Research Institute, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 03080, Republic of Korea.
  • 8 Genome & Company, 50, Changnyong-daero 256beon-gil, Yeongtong-gu, Suwon-si, Gyeonggi-do 16229, Republic of Korea.
  • 9 PeLeMed Co., Ltd., Department of Life Sciences, Gwangju Institute of Science and Technology (GIST), 123, Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Republic of Korea.
PMID: 41163312 DOI: 10.1021/acs.jmedchem.5c01391
Abstract

Tyrosylprotein sulfotransferase 2 (TPST2) was recently reported to mediate the post-translational sulfation of interferon γ (IFNγ) receptor, contributing to immunosuppression in tumor microenvironment. Herein, we report the discovery of 77c with an IC50 value of 946 nM as a novel TPST2 inhibitor through the structure-activity relationship (SAR) studies and optimization of a hit compound, 44a, identified in the enzyme-based screening of 6868 compounds from Korea Chemical Bank (KCB) library. 77c was further evaluated for its binding affinity at TPST2 and effects in IFNγ signaling in cell-based functional assays. In silico docking analysis suggested the putative binding site of 77c and key molecular interactions, providing structural insights into TPST2 inhibition. Furthermore, in the MC38 syngeneic tumor model, 77c significantly suppressed tumor growth and synergized with anti-PD-1 therapy, leading to enhanced T cell-mediated antitumor immunity characterized by increased infiltration of effector CD8+ T cells and improved systemic immune activation.

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