NP1867 (NP-1867) is a potent, first-in-class small molecule DNA mismatch repair (MMR) pathway modulator targeting PMS2 (PMS1 Homolog 2) with SPR KD of 65 nM for PMS2-N-terminal ATPase domain, IC50 of 22 nM in NanoBRET assays, blocks PMS2-NTD ATP binding site and inhibits DNA MMR.
NP1867 demonstrates potent and selective affinity for PMS2, with Ki of 101 nM in FP assays, covalently targets Cys73 in the PMS2-NTD.
NP1867 binds to the ATPase domain of hPMS2 through adduction of the Cys73 residue in the ATP binding site.
NP1867 shows no binding to MLH1 or Hsp90.
Co-treatment of WT-HAP1 cells with NP1867 and 6-TG resulted in dose-dependent inhibition of MMR-dependent DNA SSBs (EC50=43 nM), with maximal inhibition equivalent to PMS2 KO cells.
NP1867 also reduced the percentage of HAP1 cells undergoing 6-TG-induced and MMR-dependent cell-cycle arrest (G2/M cell population) and restored the percentage of proliferating cells in S-phase to that of cells not treated with 6-TG.
PMS2 inhibition by NP1867 leads to MSI-H status and MMR-d mutational signatures in cancer cells.
NP1867 pretreatment primes CRC tumours for anti-PD-1 response in vivo.