700804-58-6Relevant academic research and scientific papers
Design, synthesis and biological evaluation studies of novel small molecule ENPP1 inhibitors for cancer immunotherapy
Gangar, Mukesh,Goyal, Sandeep,Raykar, Digambar,Khurana, Princy,Martis, Ashwita M.,Goswami, Avijit,Ghoshal, Ishani,Patel, Ketul V.,Nagare, Yadav,Raikar, Santosh,Mukherjee, Apurba,Cyriac, Rajath,Paquin, Jean-Fran?ois,Kulkarni, Aditya
, (2021/12/20)
Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2′3′- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes). STING plays an important role in innate immunity by activating type I interferon in response to cytosolic 2′3′-cGAMP. ENPP1 negatively regulates the STING pathway and hence its inhibition makes it an attractive therapeutic target for cancer immunotherapy. Herein, we describe the design, optimization and biological evaluation studies of a series of novel non-nucleotidic thioguanine based small molecule inhibitors of ENPP1. The lead compound 43 has shown good in vitro potency, stability in SGF/SIF/PBS, selectivity, ADME properties and pharmacokinetic profile and finally potent anti-tumor response in vivo. These compounds are a good starting point for the development of potentially effective cancer immunotherapy agents.
