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

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.