C-271 is a first-in-class, specific small-molecule inhibitor of Thymine DNA glycosylase (TDG), inhibits TDG's glycosylase activity with similar efficacy across different substrates with IC50 of 0.16-0.25 uM, covalently targets TDG at C276.
C-271 specifically binds to TDG with a high-affinity association constant (Ka= 1.46 uM), but does not bind to other primary human glycosylase homologs (for example, UNG2 and NEIL1) or APE1 (apurinic/apyrimidinic endonuclease 1), which functions downstream of TDG in the BER.
C-271 interferes with TDG's DNA binding, thereby inhibiting its glycosylase activity.
C-271 suppresses p53-deficient tumors growth and induces cytoplasmic dsRNA accumulation in p53-deficient tumor cells.
TDG inhibition via C-271 in p53-deficient cancer cells leads to DHX9 downregulation and, thus, aberrant dsRNA accumulation, which activates the RIG-I/MDA5-MAVS sensing pathway, resulting in tumor suppression and enhanced antitumor immunity.