What question did this study set out to answer?

The aim is to identify a dual A2A/A2B adenosine receptor antagonist that can effectively combat tumor growth.

May 29, 2026

Discovery of Dual A 2A /A 2B Adenosine Receptor Antagonist and Clinical Candidate INCB106385

Puntos clave

The aim is to identify a dual A2A/A2B adenosine receptor antagonist that can effectively combat tumor growth.
Identified INCB106385 through in-house screening efforts.
Evaluated compound potency, drug-like properties, and CNS penetration.
Conducted preclinical efficacy studies in CT26 mouse colon carcinoma models.
INCB106385 shows high potency at A2A and A2B receptors with significant pharmacokinetics.
Demonstrated substantial efficacy in the CT26 mouse model, indicating strong tumor growth inhibition.
Phase 1 trials initiated under NCT04580485 and NCT04989387 support continued development.

Resumen

Suppression of immune checkpoint pathways enables tumor cells to take over immunoregulatory functions, promoting cell growth and proliferation. Elevated adenosine production in the tumor microenvironment suppresses immune checkpoint control through activation of A2A adenosine receptors on immune cells. While A2A antagonists originally developed for CNS indications have entered oncology, their potency may be insufficient to challenge locally high adenosine concentrations within the tumor microenvironment for receptor occupancy. Here, we describe the discovery of INCB106385 (36), a potent dual A2A/A2B antagonist identified from in-house screening efforts. Compound 36 exhibits high potency at both receptors, favorable drug-like properties, and limited CNS penetration. In preclinical studies, it demonstrated robust pharmacokinetics across species and significant efficacy in a multiday CT26 mouse colon carcinoma model. These findings supported the advancement of INCB106385 into Phase 1 clinical trials (NCT04580485, NCT04989387) for cancer immunotherapy.

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