Vipadenant

Based on its inhibition by antagonists, the A_2A adenosine receptor (A_2AAR) has attracted attention as an anti-tumor drug target; however, in preclinical models and clinical trials, A_2AAR antagonists have so far shown only limited efficacy as standalone therapies. The design of dual-acting compounds, targeting the A_2AAR and histone deacetylases (HDACs), is used here as an approach to the discovery of novel and more potent antitumor agents. Based on the core structures of the A_2AAR antagonists V-2006 and CPI-444, novel 4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine derivatives were designed as such dual-acting compounds. The binding affinities for A_2AAR of all the new compounds were tested, and their HDAC inhibitory activity was evaluated. Compounds with balanced A_2AAR antagonism and HDAC inhibition were tested for their in vitro anti-proliferative activity and pharmacokinetic properties. One of the compounds, 14c (4-(2-(6-Amino-4-(furan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-N-(2-amino-phenyl)benzamide) showed an overall favorable pharmacokinetic profile; in the mouse MC38 xenograft model, it showed potent anti-tumor effects with inhibition rates of 44% (90 mg/kg, po, bid) and 85% (60 mg/kg, ip, bid), respectively.

Immunometabolic modulation offers new opportunities to treat cancers as it is highly associated with cancer progression and immunosuppressive microenvironment. However, traditional regimens using nonselective small‐molecule immunomodulators lead to the off‐target adverse effects and insufficient therapeutic outcomes. Herein a second near‐infrared (NIR‐II) photothermally activatable semiconducting polymeric nanoantagonist (ASPA) for synergistic photothermal immunometabolic therapy of cancer is reported. ASPA backbone is obtained by conjugating vipadenant, an antagonist to adenosine A2A receptor, onto NIR‐II light‐absorbing semiconducting polymer via an azo‐based thermolabile linker. Under deep‐penetrating NIR‐II photoirradiation, ASPA induces tumor thermal ablation and subsequently immunogenic cell death, triggers the cleavage of thermolabile linker, and releases the antagonist to block the immunosuppressive adenosinergic pathway. Such a remotely controlled immunometabolic regulation potentiates cytotoxic T cell functions while suppresses regulatory T cell activities, leading to efficient primary tumor inhibition, pulmonary metastasis prevention, and long‐term immunological memory. Thereby, this work provides a generic polymeric approach for precise spatiotemporal regulation of cancer immunometabolism.