NP1867: A Chemical Probe for Exploring the Role of DNA Mismatch Repair in Human Disease
Time: 11:30 am
day: Day Two Track A
Details:
• MMR-deficient (MMR-d) tumors are eligible for immune checkpoint therapy, irrespective of tumors type, providing substantial clinical benefit; however, not all MMR-d patients respond to CPI therapy and correlation of tumors mutational burden with clinical outcome is controversial
• Small molecule NP1867 potently and selectively binds to the MutLa heterodimer component PMS2 enabling acute and chronic, dose- and time-dependent, MMR inhibition without removal of the target protein
• NP1867, and appropriate controls, reveal that PMS2 binding inhibits DNA Mismatch Repair in cell-based mechanistic and functional assays, elicits COSMIC mutational signatures consistent with MMR-d patient populations, and renders treated tumour cells immunogenic
