Identification of Novel Oxazolo[5,4-d]pyrimidines as IL-33 Inhibitors for Immuno-Oncology Therapy.

Area of Science:

• Immunology
• Cancer Biology
• Drug Discovery

Background:

• The IL-33/ST2 signaling pathway promotes immune suppression in the tumor microenvironment via regulatory T (Treg) cells.
• Elevated IL-33 correlates with poor cancer prognosis by enhancing Treg stability, proliferation, and function, thus hindering antitumor immunity.

Purpose of the Study:

• To design and evaluate novel small-molecule inhibitors targeting the IL-33/ST2 axis.
• To suppress Treg-mediated immune evasion and enhance antitumor responses.

Main Methods:

• Structure-based drug design was employed to identify oxazolo[5,4-d]pyrimidine derivatives targeting the IL-33 binding pocket.
• In vitro and ex vivo assays assessed compound efficacy on T-Cell Receptor (TCR)-stimulated human Treg cells.

Main Results:

• Novel small molecules demonstrated significant suppression of IL-33-induced Treg activation and proliferation.
• Compound KYH1942 potently reduced IL-33-induced Foxp3 and Ki-67 expression, indicating impaired Treg function.
• Inhibitory activity was comparable to neutralizing ST2 antibodies.

Conclusions:

• This study presents the first small-molecule IL-33 blockade directly suppressing Tregs, including IL-33-driven Foxp3 and Ki-67 expression.
• These findings establish a novel immunotherapeutic strategy targeting IL-33-mediated immune suppression in cancer.