Next generation "synthetic lethal" ATR inhibitors are being developed

IMP9064, an ATR inhibitor, has been approved for phase I/II clinical trial by the U.S. Food and Drug Administration (FDA). This is the first time that an ATR inhibitor from IMP9064 has entered clinical trial phase. ATR is a synthetic lethal target for ATM mutations, and is considered to be one of the most promising synthetic lethal targets after PARP. At present, there are many ATR inhibitors in clinical phase II around the world.

Brief introduction of ATR targets
ATR stands for ataxia telangiectasia and RAD3-related telangiectasia mutations, which are composed of 2644 amino acids and are capable of activating cellular responses after DNA damage. It further blocks cell cycle progression, stabilizes replication forks and repairs DNA, thereby avoiding the important kinases of apoptosis. When DNA replication pressure and DNA damage occur in cells, ATR is recruited to the site of DNA damage, and a variety of proteins are involved in regulating the activation of ATR. When activated, ATR can regulate cellular biological processes through a variety of signals, including cell cycle arrest, inhibition of replication origin, promotion of deoxynucleotide synthesis, initiation of replication fork and repair of DNA double-strand breaks.

Due to defects in various DNA repair pathways in tumor cells, tumor cells are more dependent on ATR repair pathways and more sensitive to ATR inhibitors than normal cells. "Synthetic death" means that in tumor cells, due to defects caused by mutations in one pathway, tumor cells are more dependent on another complementary pathway than normal cells, so inhibition of the complementary pathway will result in "synthetic death" to tumor cells. Normal cells, on the other hand, do not die because there is a pathway that is normal. ATR is a synthetic lethal target for some mutations. For example, atR-deficient tumor cells are more sensitive to ATR inhibitors, and the loss of X-ray cross-complementary repair gene ⅰ also makes tumor cells more sensitive to ATR inhibition. Therefore, ATR inhibitors are expected to be excellent potential drugs for tumor therapy due to their selective effect on tumor cells and less interference on normal cells.

Figure: Diagram of synthetic death

ATR inhibitors are considered as one of the most promising synthetic lethal targets after PARP inhibitors, and are new therapeutic agents for PATIENTS with ATM mutations. At present, no ATR inhibitor has been approved for marketing in the world, and Merck, Astrazeneca, Repare Therapeutics and other companies have advanced ATR inhibitor clinical progress, currently in phase II clinical. According to the disclosed clinical data, THE safety of ATR inhibitors is controllable, and they show good anti-tumor activity against solid tumors, and the future prospects are very broad. There are only a few ATR inhibitors in China. IMP9064 from Inpidupharma was recently approved by FDA for clinical trials. In addition, ATR inhibitors from Merck and Bayer have been approved by NMPA and are currently in phase I clinical trials.