PARP Inhibitor

In healthy cells, DNA damage occurs and is repaired by Cancer cells also experience proteins, such as poly ADP-ribose polymerase (PARP), damage to their DNA, just like so the cell can continue to function. This damage can be healthy cells, and use proteins spontaneous or the result of environmental factors like such as PARP to repair the radiation or some chemicals.i damaged DNA.ii

Mechanism of Action*

Single Strand Break (SSB) SSB converts to Double Strand Break (DSB)

PARP recruited; PARylation initiation PARP Ribosylation inhibition PARP1 PARP1 PARP1 Replication fork collapses

HRD tumors (may be BRCAmut or BRCAwt) PARP inhibition Accumulation of DNA damage Accumulation of DNA damage Cell Cell Death Death

DSB: Double strand break HRD: Homologous recombination deficiency Platinum causes DSB PARP: Poly ADP-ribose polymerase P PR: Partial response SSB: Single strand break

PARP Replication forks collapse at additional inhibition sites of damage PARP inhibitors block the PARP protein. That means the damaged DNA can’t be PARP1

repaired in the cancer cell, so PARP1 the DNA accumulates more and more damage, turning PARP inhibition from single-strand breaks to causes more DSBs double strand breaks. This accumulation can lead to the death of the cancer cell.ii Cell Accumulation of DNA damage Death

*As understood through pre-clinical evidence.

References i Davar D, Beumer JH, Hamieh L, Tawbi H. Role of PARP inhibitors in cancer biology and therapy. Curr Med Chem. 2012;19(23):3907-3921. ii Jubin T, Kadam A, Jariwala M, et al. The PARP family: insights into functional aspects of poly(ADP-ribose) polymerase-1 in cell growth and survival. Cell Prolif. 2016;49(4):421-437.

NP-GBL-NRP-OGM-200001 / March 2020