Discovery of a Potent and Selective CCR4 Antagonist That Inhibits T_reg Trafficking into the Tumor Microenvironment

Area of Science:

• Immunology
• Oncology
• Medicinal Chemistry

Background:

• Tumor-infiltrating regulatory T cells (Treg), expressing CCR4, can suppress anti-tumor immunity in patients undergoing immuno-oncology (IO) therapy.
• Recruitment of Treg cells is mediated by chemokines CCL17 and CCL22, and their accumulation often correlates with poor prognosis in certain cancers.
• Preclinical studies suggest that inhibiting Treg recruitment can enhance anti-tumor responses by increasing effector T cell populations.

Purpose of the Study:

• To develop novel, orally bioavailable small molecule antagonists of CCR4.
• To investigate the potential of these antagonists in preventing Treg recruitment to the tumor microenvironment (TME).
• To evaluate the impact of CCR4 antagonism on potentiating anti-tumor immune responses.

Main Methods:

• Design and synthesis of a novel series of small molecule CCR4 antagonists.
• Evaluation of compound potency in functional assays and assessment of in vitro/in vivo ADME properties.
• Structure-Activity Relationship (SAR) studies and confirmation of in vivo anti-tumor activity.

Main Results:

• Several potent, orally bioavailable CCR4 antagonists were identified from the novel series.
• Compounds demonstrated high potency in functional assays and favorable ADME profiles.
• In vivo studies confirmed the efficacy of the developed compounds.

Conclusions:

• The developed small molecule CCR4 antagonists represent a promising therapeutic strategy.
• These compounds have the potential to enhance anti-tumor immunity by modulating Treg cell infiltration.
• Further development could lead to improved immuno-oncology treatments for cancer patients.