Second messenger 2'3'-cyclic GMP-AMP (2'3'-cGAMP): the cell autonomous and non-autonomous roles in cancer progression

Discovery of Pyrido[2,3-d]pyrimidin-7-one Derivatives as Highly Potent and Efficacious Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Cancer Treatment

“…As such, a continuous endeavor is underway to discover methods for transforming the “cold” tumors into immunologically “hot” tumors with high T cell responsiveness. , One such mechanism is the activation of the stimulator of interferon genes (STING) pathway, which is a strategy for enhancing host immune surveillance and remodeling the tumor microenvironment (TME) . STING can be allosterically triggered by the cyclic guanosine monophosphate-adenosine monophosphate (cGAMP or cyclic GMP-AMP), which is generated by cyclic GMP-AMP synthase (cGAS) in response to cytosolic DNA associated with viral infections and tumor proliferation. – Upon binding to cGAMP, STING initiates TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) signaling cascade in tumor and host immune cells and promotes production of type I interferons (IFNs) and infiltration of tumor-infiltrating lymphocytes (TILs), ultimately leading to antitumor immunity. , STING agonists have shown promising antitumor effects in preclinical studies. – However, their systemic administration has not demonstrated the desired clinical efficacy and safety, possibly due to unfavorable pharmacokinetic properties and hyperactivation of the STING pathway. – Thus, an improved approach is needed to deliberately modulate the STING pathway in cancer therapy . Recent studies demonstrated that one novel strategy to restore the STING activation involves the inhibition of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1, formerly known as NPP1 or PC-1), a natural antagonist of the STING pathway. – …”