Synthetic lethality: who will share the share of the PARP inhibitor market in the future?

What other targets and pathways can be expected?

Since the success of PARP inhibitors, a large number of domestic and foreign resources have been invested in the research of synthetic lethal theory in order to obtain better tumor treatment drugs.
The more popular targets for research mainly include two corresponding pathways, ATR and ATM
.

Ataxiat elangiectasia-mutated kinase (ATM)/checkpoint kinase 2 (Chk2) and ATR (ATM and rad3· related kinase, ATR)/Chk 1 (checkpoint kinase 1, Chk1) pathway is two important DNA repair pathways
.

ATM can be activated by ionizing radiation, radiotherapy, and drugs that cause DNA double-strand damage.
ATM can phosphorylate and activate the Ser216 site of Chk2 and Cdc25c phosphatase to generate a site that can bind to a specific protein to block cdc25c phosphatase from entering and exiting the nucleus.
The import and export of cytoplasm effectively inactivate the activity of cdc25c phosphatase, leaving CDKl in a non-functional state, and the CDKl/Cvclin B complex is also inactive, and the cell cycle cannot enter the mitotic phase
.

In addition, ATR can be activated depending on ATM activation
.
In the process of double-strand DNA breaks, ATR is the main kinase responsible for phosphorylation and activation of Chkl.
Compared with Chk2, Chkl can be activated by ATM and ATR at the same time, which can occur during the normal cell cycle or in response to cell replication.
Under stress (such as in the replication fork stagnation period), Chkl can simultaneously phosphorylate and activate weel protein kinase and Cdc25c phosphatase, and weel protein kinase phosphorylates the Tyrl5 site of CDKl/Cyclin B complex CDKl, causing it to inactivate.
The cell cycle is arrested in the G2 phase and DNA repair is performed
.
cdc25c phosphatase can dephosphorylate the Tyr15 site of CDK1 to restore its activity, resulting in the cell cycle entering M phase
.

In recent years, for the above-mentioned related targets, many varieties have entered the clinic, and the progress is rapid.
Many varieties have entered clinical phase III and phase II, and most of the development companies are large global pharmaceutical companies, such as Aspen Likang, Merck, Pfizer, etc.
; and domestic companies are also committed to deep digging in the field of synthetic lethality, and currently existing varieties have entered the clinical phase I, in order to achieve rapid simultaneous listing
.

summary

The success of PARP inhibitors has allowed researchers to see the potential clinical value of synthetic lethality, especially that it can solve many clinical problems that traditional targeted drugs cannot solve
.
Regardless of whether it is a large foreign pharmaceutical company or some new innovative drug research and development companies listed in China, they have formed a product and intellectual property layout in this direction
.
However, the varieties currently under research are still relatively concentrated, especially in the research and development of new drugs in China.
Most of them hope to achieve fast-follow.
The research and development of more creative products still needs to go further.
It is really close to the first in class.
Distance
.

Reference materials:

EMBO, 2017, 36(14): 2161-2176.

J.
Med.
Chem.
2020, 63, 14151?14183.

curr Probl cancer, 2017, 4l(4): 302-315.

J Biol chem, 2017, 292(30): 12424-12435.

Application of synthetic lethality in precision oncology.
Science Bulletin, 2018, 63: 1123-1129.