Discovery of Benzocyclic Sulfone Derivatives as Potent CXCR2 Antagonists for Cancer Immunotherapy
Yi Dong1,2, Rong Fu1, Jiajing Chen1,2
1State 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.
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.
Insights
New drug candidates targeting the CXCR2 pathway show promise in cancer immunotherapy by reducing myeloid-derived suppressor cells and enhancing anti-tumor T cell responses. These compounds inhibit tumor growth and immune suppression.
Area of Science:
- Oncology
- Immunology
- Medicinal Chemistry
Background:
- The CXC chemokine receptor 2 (CXCR2) pathway drives myeloid-derived suppressor cell (MDSC) infiltration and immune suppression in the tumor microenvironment.
- CXCR2 antagonists represent a potential therapeutic strategy for enhancing cancer immunotherapy.
Purpose of the Study:
- To design and synthesize novel benzocyclic sulfone derivatives as potent CXCR2 antagonists.
- To evaluate the efficacy of these compounds in preclinical cancer models.
Main Methods:
- Structure-activity relationship studies were conducted to identify lead compounds.
- Compounds were tested for CXCR2 antagonism and inhibition of neutrophil infiltration in vivo.
- Antitumor activity was assessed in the Pan02 mouse model following oral administration.
- Flow cytometry and immunohistochemistry were used to analyze immune cell infiltration in tumors.
Main Results:
- Two lead compounds, 9b and 11h, exhibited double-digit nanomolar potency against CXCR2.
- Compounds 9b and 11h significantly inhibited neutrophil infiltration in an air pouch model.
- Oral administration of 9b and 11h dose-dependently suppressed tumor growth in the Pan02 model.
- Treatment reduced neutrophil and MDSC infiltration while increasing CD3+ T lymphocyte infiltration in tumor tissues.
Conclusions:
- Benzocyclic sulfone derivatives targeting CXCR2 are effective in reducing MDSC-mediated immunosuppression.
- Compounds 9b and 11h demonstrate significant potential as orally available agents for cancer immunotherapy.
- These findings elucidate the mechanism of action, involving modulation of immune cell populations within the tumor microenvironment.
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