Synthesis and Biological Evaluation of Peripheral HTR2A Antagonists for Colorectal Cancer

  • J Med Chem. 2025 Jan 23;68(2):1716-1730. doi: 10.1021/acs.jmedchem.4c02458.
Minhee Kim  1  2 ,  Jihyeon Yoon  1 ,  Jun Young Choi  3 ,  Geumi Park  3 ,  Jae-Eon Lee  3 ,  Gwi Bin Lee  1 ,  Byeong Wook Choi  1 ,  Pyeongkeun Kim  1 ,  Hail Kim  4 ,  Chang-Myung Oh  5 ,  Myung Ae Bae  2 ,  Seong Soon Kim  2 ,  Eun Young Lee  6 ,  Hyeok Jae Lee  1 ,  Yunmin Kim  1 ,  Hyun Woo Kim  1  7 ,  Hohjai Lee  1 ,  Yong Hyun Jeon  3 ,  Jin Hee Ahn  1  6
Affiliations
  • 1. Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
  • 2. Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 3. Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDIhub), 80 Cheombok-ro Dong-gu, Daegu 41061, Republic of Korea.
  • 4. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
  • 5. Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
  • 6. JD Bioscience Inc., TJS Knowledge Industrial Center Suite 801, 208 Beon-gil Cheomdangwagi-ro, Buk-gu, Gwangju 61011, Republic of Korea.
  • 7. Center for Quantum Technology, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
PMID: 39760275 DOI: 10.1021/acs.jmedchem.4c02458
Abstract

Colorectal Cancer is a prevalent and prominent contributor to global cancer-related fatalities with challenges in drug resistance and metastasis. Recent research highlights the potential relationship between serotonin and Cancer. 5-Hydroxytryptamine receptor 2A (HTR2A) mRNA expression in colorectal Cancer cells was found to be notably elevated compared to that in normal colon cells. We therefore attempted to synthesize and evaluate HTR2A antagonists to find peripherally acting Anticancer agents. Among them, 15f showed good in vitro activity (IC50: 42.79 nM). 15f revealed good liver microsomal stability, without significant CYP inhibition and limited blood-brain barrier penetration. 15f also exerted selective cytotoxic effects against various colorectal Cancer cells but not normal cells. 15f induced sub-G1 cell cycle arrest and Apoptosis in colorectal Cancer cells via the activation of p53/p21/Caspase 3 signaling. In vivo treatment with 15f led to a marked delay in tumor growth in a colorectal Cancer model in a dose-dependent manner.

Products