M1069 is a selective and orall active, dual A2A/A2B adenosine receptor antagonist with a selectivity of >100 fold against the A1 and A3 receptors. M1069 counteracts immune-suppressive mechanisms of adenosine, and exhibits anti-tumor activity.
Metabolically stressful conditions, including inflammation and cancer, induces extracellular concentrations of adenosine increase[1].M1069 dose-dependently suppresses 5’-N-etlcarboxamide adenosine (stable analog of adenosine)-stimulated cyclic adenosine monophosphate (cAMP) and phosphorylated cAMP- response element binding protein (pCREB) induction, inhibits interleukin (IL)-2 production[1].M1069 suppresses vascular endothelial growth factor (VEGF) production from human macrophages in adenosine-rich settings[1].M1069 inhibits protumorigenic cytokine secretion, such as CXCL1, CXCL5 and granulocyte-colony stimulating factor, and reduces IL-12 secretion from adenosine-differentiated dendritic cells[1].M1069 enhances T-cells activation in adenosine-differentiated dendritic cells[1].
M1069 inhibits breast tumor (CD73hi/adenosine-rich 4T1 syngeneic) growth in vivo in mice and enhances chemotherapeutic agents efficacy[1].
References:
[1]. Rinat Zaynagetdinov, et al. Abstract 3499: M1069 as dual A2A/A2B adenosine receptor antagonist counteracts immune-suppressive mechanisms of adenosine and reduces tumor growth in vivo. Cancer Res (2022) 82 (12_Supplement):3499. [2]. Lillian L Siu, et al. Abstract CT240: A first-in-human study of the dual A2A/A2B adenosine receptor antagonist M1069 in patients with advanced solid tumors. Cancer Res (2022) 82 (12_Supplement):CT240. [3]. Tanzer Eva-Maria, et al. Preparation of thiazolopyridine derivatives as adenosine receptor antagonists: World Intellectual Property Organization, WO2020152132[P]. 2020-07-30.