2. Academic Validation
  3. Discovery of Benzocyclic Sulfone Derivatives as Potent CXCR2 Antagonists for Cancer Immunotherapy

Discovery of Benzocyclic Sulfone Derivatives as Potent CXCR2 Antagonists for Cancer Immunotherapy

  • J Med Chem. 2021 Nov 25;64(22):16626-16640. doi: 10.1021/acs.jmedchem.1c01219.
Yi Dong 1 2,  Rong Fu 1,  Jiajing Chen 1 2,  Kehui Zhang 1 2,  Ming Ji 1,  Mingjin Wang 1,  Huimin Jiang 1,  Wei Ye 1 2,  Jinping Hu 3,  Yan Li 3,  Jing Jin 1,  Xiaoguang Chen 1,  Heng Xu 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3 Beijing Key Laboratory of Non-clinical Drug Metabolism and PK/PD Study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 34676759 DOI: 10.1021/acs.jmedchem.1c01219
Abstract

Increasing evidence shows that the CXC Chemokine Receptor 2 (CXCR2) signaling pathway is essentially implicated in the recruitment of myeloid-derived suppressor cells (MDSCs) to the tumor microenvironment and leads to MDSC-mediated immune suppression. Therefore, CXCR2 has recently emerged as a promising drug target for Cancer Immunotherapy. In this paper, benzocyclic sulfone derivatives were designed as potent CXCR2 antagonists. Structure-activity relationship studies resulted in two lead compounds 9b and 11h, which demonstrated double-digit nanomolar potencies against CXCR2 and significantly inhibited neutrophil infiltration into the air pouch in an in vivo setting. More importantly, 9b and 11h dose-dependently inhibited the tumor growth through oral administration in the Pan02 mouse model. Further cytometry and immunohistochemical analyses revealed that 9b and 11h could reduce the infiltration of neutrophils and MDSCs and enhance the infiltration of CD3+ T lymphocytes into the Pan02 tumor tissues, shedding light on their mechanisms of action in Cancer Immunotherapy.

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