The tumor microenvironment is characterized by conditions that frequently lead to immunosuppression, allowing tumors to escape immune surveillance and potentially contributing to resistance to immuno-oncology therapeutics. A potential strategy for combination therapy with checkpoint inhibitors is to target the A2A and A2B receptors with a dual antagonist that could rescue T cells from adenosine-mediated suppression. Herein, we describe efforts toward highly potent and selective A2A/A2B dual receptor antagonists with improved pharmacokinetic and solubility profiles compared to initial lead compounds. We discovered that a 1,3-cyclobutane linker between our triazoloquinazoline core and a pendant aryl substituent decorated with a tertiary carbinamine provided a desirable balance of potency and physicochemical properties. Our lead molecule 34 demonstrated an exceptional effective half-life across multiple species. Chemistry advances guided by high-throughput experimentation (HTE) facilitated efficient, late-stage access to complex derivatives in this series.
Brill et al. (Tue,) studied this question.