When will the immune check be launched all over the world for protein kinase checkpoints?

Immune checkpoint inhibitors have won the clinical and market in the past 5 years.

Chk1 target characteristics

Structurally, the human Chk1 (check point kinase 1) gene encodes a protein kinase with 476 amino acids and a molecular weight of 54kD; it includes four domains: N-terminal kinase domain, variable junction domain, regulatory domain and inhibitory domain

Figure 1.

(Image source: PDB database)

The association between Chk1 and tumors is mainly related to DNA damage response (DDR)

When DNA is stimulated by damage, it will slow down or stall the replication fork, exposing single-stranded DNA (ssDNA), which is bound by replication protein A (RPA), causing some proteins to accumulate on the stalled replication fork and activate the protein kinase ATR , the ATR kinase activated by phosphorylation of its effect Chk1, Chk1 phosphorylation of target cells to perform DNA replication checkpoint function of pressure, covers cell cycle arrest or stopping the replication fork stability, control release and replication origin of replication points reboot

At a further molecular level, the ATR-Chk1 pathway can recognize more extensive DNA damage than the ATM-Chk2 pathway

Figure 1.

(Image source: Radiotherapy and Oncology)

Structure and function of Chk2

Compared with Chk1, the human Chk2 gene can encode a serine/threonine protein kinase with a molecular weight of 60kD and 543 amino acids.

When DDR occurs in DNA, especially DNA double-strand breaks (DSBs), the check sites corresponding to the three periods of G1/S, S, and G2/M can be activated through the ATM-Chk2-Cdc25 signaling pathway , To repair DNA damage and block the cell cycle process; if the DNA damage is not repairable, Chk2 kinase can also induce DNA damage cell apoptosis.

Figure 2.

(Image source: PDB database)

Global development of Chk1 protein kinase inhibitors

Chemotherapy and radiotherapy will damage the DNA of tumor cells to a certain extent, thereby killing the proliferating tumor cells; at the same time, activate the DDR and cell cycle checkpoints that depend on related protein kinases to resist this damage and maintain the tumor cells.

Table 3.

Introduction of specific clinical varieties

As mentioned above, currently no Chk1 protein kinase inhibitor has been approved for marketing.

SCH900776(MK-8776)

The development company is Merck, a highly selective inhibitor of Chk1 protein kinase, which can weaken the repair ability of DNA in cancer cells

In addition, MK-8776 can enhance the sensitivity of human colon cancer cells to the cytotoxic effects of cisplatin and platinum complexes.

LY2606368 and LY2603618

The development company is Eli Lilly and Company.

LY2603618, also a highly selective Chk1 kinase inhibitor, is mainly used as a chemotherapy sensitizer in tumor treatment
.
It has entered a phase II trial in non-small cell lung cancer, which can improve the progression-free survival of patients
.
It produced a significant effect in many tumors, such as: malignant melanoma, mantle cell lymphoma, nasopharyngeal carcinoma and the like
.

AZD7762

The development company is AstraZeneca, which is an ATP directly competitive Chk1/2 protein kinase inhibitor, which can effectively inhibit the phosphorylation of Chk1 of the cdc25c peptide with an IC50 value of 5nM and a Ki value of 3.
6nM
.
In the KRAS/p53/LKB1 cell line and the mouse model of lung cancer induced by KRAS/p53/LKB1, the DNA of tumor cells has a high rate of damage, which enhances the function of Chk1 protein kinase-dependent checkpoints.
Use AZD7762 to damage DNA Co-treatment with the drug gemcitabine can reduce tumor size in these models, especially in the extremely aggressive and aggressive LKB1 lung adenocarcinoma
.
In terms of clinical trials, it is mainly combined with gemcitabine and irinotecan for safety, tolerability, and related dose-climbing tests
.

Summary and thoughts

In summary, it is generally the current development of protein kinase checkpoint inhibitors
.
In general, the advancement of drugs in this direction is under steady research, and there is no clinical breaking point data; like synthetic lethal drugs, stronger clinical data are needed to prove it
.
However, the global sales growth of PARP inhibitors in the synthetic lethal field in recent years is stimulating the development of this online drug.
Once a clinical breakthrough is formed, blockbuster-level varieties will inevitably be born.
Overall, it is still worthy of attention and expectation.

.

Reference source:

1.
Radiotherapy and Oncology, 2017.
doi.
org/10.
1016/j.
radonc.
2017.
09.
043

2.
https://www1.
rcsb.
org/3d-view/2YDJ/1

3.
https://www1.
rcsb.
org/3d-view/2W0J/1

4.
https://clinicaltrials.
gov/

5.
CNKI Date