The next generation of "synthetic lethal" ATR inhibitors are being developed

Recently, Impair Pharmaceuticals announced that the company's ATR inhibitor IMP9064 has obtained the U.
S.
Food and Drug Administration (FDA) Phase I/II clinical trial approval.
This is the first time that Impair Pharmaceuticals ATR inhibitor has entered the clinical trial stage
.
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
.
01 Introduction to ATR Targets ATR's full name is ataxia telangiectasia and Rad3-related kinase (ataxia telangiectasia and Rad3-related), which is composed of 2644 amino acids, which can activate cell responses after DNA damage, thereby blocking the cell cycle Process and stabilize the replication fork and repair 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 ATR is activated, it can regulate cell biological processes through a variety of signals, including cell cycle arrest, inhibition of the origin of replication, promotion of deoxynucleotide synthesis, initiation of replication forks, and repair of DNA double-strand breaks
.
Figure: ATR pathway Due to the defects of multiple DNA repair pathways in tumor cells, tumor cells are more dependent on the ATR repair pathway and are more sensitive to ATR inhibitors than normal cells
.
"Synthetic lethality" refers to the defect caused by mutation of one pathway in tumor cells, which makes tumor cells more dependent on another complementary pathway than normal cells.
Therefore, inhibiting the complementary pathway will cause "synthetic lethality" to tumor cells
.
However, normal cells will not die under drug inhibition because there is another pathway that is normal
.
Studies have found that ATR is a synthetic lethal target for partial mutations.
For example, tumor cells with missing ATM are more sensitive to ATR inhibitors, and the loss of X-ray staggered complementary repair gene I will also cause tumor cells to be more sensitive to ATR inhibition..
Therefore, ATR inhibitors are expected to become excellent potential drugs for tumor treatment due to their selective effects on tumor cells and less interference with normal cells
.
Figure: Synthetic lethal diagram 02 ATR inhibitors at a glance As the most promising "synthetic lethal" therapy after PARP inhibitors, ATR inhibitors have attracted a number of multinational giants, including Merck, Bayer, AstraZeneca, etc.
Berzosertib of the company is in the leading clinical progress and is currently in clinical phase II
.
There are few companies deploying ATR inhibitors in China.
IMP9064 was approved by the FDA for phase I/II clinical research on October 29.
The ATR inhibitors that have been approved by NMPA for clinical trials include Merck’s Berzosertib, Bayer’s BAY1895344 and Bayer’s BAY1895344.
Shijiazhuang chi Kanghong Ren a new drugs ATR inhibitors are in clinical stage ⅰ
.
(1) Berzosertib (VX-970, M6620) is a pioneering, potent and selective ATR inhibitor developed by Merck, currently in clinical phase II
.
On April 12, 2021, Merck announced the results of a phase II clinical trial of Berzosertib.
In recurrent small cell lung cancer, the objective remission rate of Berzosertib combined with the chemotherapy drug topotecan reached 36%, platinum-sensitive and platinum-resistant Remission was observed in all patients with the drug
.
The median duration of response (DoR) was 6.
4 months, the median progression-free survival (PFS) was 4.
8 months, and the median overall survival was 8.
5 months
.
In terms of safety, the most common grade 3 or 4 AEs are lymphopenia (69.
2%), thrombocytopenia (57.
7%), anemia (53.
8%) and centrocytopenia (15.
4%).
Most AEs are attributable to Topotecan
.
In addition, in 2020, Merck announced in The Lancet the results of a clinical trial of Berzosertib combined with gemcitabine in the treatment of patients with advanced ovarian cancer
.
The data showed that the mPFS of the Berzosertib combined with gemcitabine group was 22.
9 weeks, while the mPFS of the gemcitabine single-agent group was only 14.
7 weeks
.
In terms of safety, adverse events in the combination group were significantly higher than those in the single-agent group.
Grade 3-4 TRAEs included decreased neutrophil count (47% vs 39%) and decreased platelet count (24% vs 6%).
One patient died of pneumonia
.
In general, Berzosertib combined with gemcitabine in the treatment of ovarian cancer showed a significant improvement in progression-free survival, but the safety still needs further observation
.
Figure: Berzosertib chemical structure (2) Ceralasertib (AZD6738) is a selective ATR inhibitor developed by AstraZeneca with IC50 of 1nM
.
In p53 or ATM-deficient cells, treatment with Ceralasertib causes the stop of replication forks and the accumulation of unrepaired DNA damage, leading to mitotic disorders, which can lead to tumor cell death
.
In May 2021, AstraZeneca released the results of a phase I clinical trial of Ceralasertib combined with paclitaxel in "Clinical Caner Research"
.
The trial included 57 tumor patients, including 15 cases of gastric cancer, 4 cases of sarcoma, 3 cases of colon cancer, 1 case of neuroendocrine tumor, and 33 patients with melanoma who had progressed after treatment with PD-(L)1 inhibitors
.
The test results showed that the total ORR of Ceralasertib combined with paclitaxel treatment reached 22.
6%, of which the melanoma subgroup achieved an objective remission rate of 33.
3%, mPFS reached 3.
6 months, mDoR reached 9.
9 months, and mOS reached 7.
4 months
.
In terms of adverse reactions, common adverse reactions include neutropenia (68%), anemia (44%) and thrombocytopenia (37%)
.
In general, the safety of Ceralasertib is controllable, and as the treatment progresses, the expression of PD-(L)1 in the tumor tissues of patients gradually increases, which indicates that ATR inhibitors are expected to convert patients who do not respond to PD-L1 treatment to PD -Patients with high expression of L1
.
In future research, the combination with immune checkpoint inhibitors may be an important direction for ATR inhibitors
.
FIG: AZD6738 chemical structure (3) BAY1895344 developed by Bayer, is a highly efficient, highly selective inhibitors of ATR orally, an IC50 of 7 nM, currently in clinical stage Ⅰ
.
In 2020, in the "Cancer Discovery" magazine, Bayer disclosed the early clinical data of BAY1895344.
The trial included 22 patients with advanced solid tumors.
The ORR reached 18.
18% (4/22), the DCR reached 54.
54% (12/22), and the mDoR.
Up to 315.
5 days, the responders all had ATM protein loss or ATM mutation
.
In terms of safety, common TRAEs are anemia (81.
8%, all grade 3), neutropenia (72.
7%, grade 3/4 up to 54.
5%) and thrombocytopenia (45.
5%, grade 3/4 up to 18.
2%)
.
In general, BAY1895344 has good anti-tumor activity for ATM-mutated solid tumors
.
Figure: BAY1895344 chemical structure (4) Impair Pharmaceuticals focuses on the synthesis of lethal mechanisms.
The company's product pipeline includes PARP inhibitors, Wee1 inhibitors and many other DDR target inhibitors
.
IMP9064 is an ATR inhibitor independently developed by the company.
Preclinical data shows that IMP9064 has high inhibitory activity on ATR and also shows high selectivity compared to other kinases.
At the same time, IMP9064 is both in ATM-deficient cell lines and transplanted tumor models.
Shows strong anti-tumor activity, higher in vivo activity than similar products, and has the potential to obtain a wider treatment window, as well as long-term single-drug and combination drugs
.
On October 29, 2021, Impair Pharmaceuticals announced that IMP9064 was approved by the US Food and Drug Administration (FDA) for Phase I/II clinical research
.
03 Summary ATR inhibitors are considered to be one of the most promising synthetic lethal targets after PARP inhibitors, and are new therapeutic drugs for patients with ATM mutations
.
At present, no ATR inhibitor has been approved for marketing in the world.
The clinical progress of ATR inhibitors from companies such as Merck, AstraZeneca, and Repare Therapeutics are among the highest in clinical progress, and they are currently in phase II clinical trials
.
According to the currently disclosed clinical data, the safety of ATR inhibitors is controllable and shows good anti-tumor activity against solid tumors.
The future prospects are very broad
.
There are few domestic companies with ATR inhibitors.
IMP9064 has recently been approved by the FDA for clinical trials.
In addition, Merck and Bayer's ATR inhibitors have been approved by NMPA and are currently in phase I clinical trials
.