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Power target Polθ: potential bursts, giants enter the game

 Last Update: 2021-08-28
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On August 5, Artios Pharma publicized the clinical registration information of the First in class drug ART4215 on the clinicaltrials website, and ART4215 became the world's first DNA polymerase θ (Pol θ/POLQ) inhibitor to enter clinical trials
.

DNA polymerase theta (Polθ or POLQ) is a synthetic lethal target with homologous recombination (HR) defects, and plays an important role in the DNA damage response (DDR) pathway of double-strand breaks (DSB)
.

DDR has been an area of great concern for domestic and foreign pharmaceutical companies in recent years.

Although Polθ, as a target that has attracted much attention in this field, its development has been slightly slow; however, it has also received frequent attention from giants
.

GSK has reached a POLQ development agreement with IDEAYA and is currently in the preclinical stage

POLQ: Synthesis of lethal potential targets in the DDR field

The theory of synthetic lethality has a long history and can be traced back to 1922 [1].
The PARP inhibitor olaparib is the first synthetic lethality drug to obtain proof of concept in clinical and practice
.

The DNA polymerase theta (POLθ or POLQ) belongs to the synthetic lethal category of homologous recombination (HR) defects, and therefore, it has become a candidate target for HR-deficient cancers

In 2003, Shima N et al.
found that the mutation of mouse Chaos1 (spontaneous chromosome aberration 1) caused the main amino acid in Polq1 gene to change from serine to proline.
This discovery opened the origin of research on Pol θ[2]
.

Since then, Wood's laboratory has purified the full-length human Polθ and confirmed that it has DNA synthesis and DNA-dependent ATPase activity [3]

Schematic diagram of Polθ[4]
.

The superfamily 2 (SF2) helicase domain contains a conserved nucleotide binding site (NT, dark gray), a conserved DEAH box motif (DEAH, dark gray), and a conserved C-terminal helicase Structural domain (Helicase-C, dark gray)

Schematic diagram of Polθ[4]

When DNA ends are excised, in the presence of BRCA2, BRCA2 not only recruits the recombinase RAD51 to DSB to promote HR, but also inhibits repair pathways such as alt-NHEJ
.

Source: IDEAYA

When homologous recombination-mediated repair is damaged (HR defect), such as BRCA1 or BRCA2 mutations, Polθ is highly expressed and guides DSB repair toward alt-EJ, opening the DNA repair process of micro-homology-mediated end joining (MMEJ)
.

In the case of HR deficiency, the inhibition of Polθ leads to cell death through the accumulation of toxic RAD51 intermediates and the inhibition of the alt-EJ repair pathway [6]

Source: Reference 6

In addition, Polθ also has reverse transcription of RNA and promotes DNA repair using RNA as a template [7]
.

Polθ is almost not expressed in normal tissues, but is highly expressed in a variety of tumor types (such as breast cancer, ovarian cancer, HNSCC, and lung cancer)

ART4215: Potential bursts, clinical opening

According to the data of NextPharma, the ART4215 developed by Artios is the first and only clinical Polθ inhibitor, and related projects such as Ideaya and Repare are also being carried out
.

In particular, Ideaya and GSK are developing a variety of strategies for the Polθ project, and have already released some Polθ inhibitor data; according to the project information just updated this month, Ideaaya has shifted its strategy to Polθ degradants
.
Of course, in addition to Polθ inhibitors, Ideaya is also conducting research on synthetic lethality projects for multiple other targets
.

Novartis is also another pharmaceutical giant focusing on DDR besides GSK
.
In April 2021, Novartis and Artios reached a cooperation agreement of up to US$1.
3 billion to discover and validate next-generation DDR projects and enhance the clinical potential of Novartis radioligand therapy (causing DNA damage), such as 177Lu-PSMA-617
.
Prior to this, Merck also reached a cooperation agreement with Artios in the DDR field of up to US$860 million
.

Although, ART4215 currently has less public information; however, Artios published the preclinical data and research status of selective small molecule Polθ polymerase inhibitors on Nature Communications in June this year [8]
.
In view of the fact that ART4215 developed by Artios is the only Polθ inhibitor that has entered clinical development, and Artios' patented layout also includes an ART588 type skeleton
.
Therefore, choose this article for a brief introduction
.

Unlike Ideala, Artios disclosed in this article a class of highly active and selective small molecule Polθ polymerase allosteric inhibitors
.
In addition, it was revealed that ART558 caused DNA damage and synthetic lethality in BRCA1 or BRCA2 mutant tumor cells, and enhanced the effect of PARP inhibitors
.

The structure and biochemical IC50 activity of Polθ inhibitor ART558 and inactive isomers (source, reference 8)

In in vitro experiments, ART558 showed non-competitive inhibition of dNTP and DNA, indicating that ART558 binds to the allosteric site in the polymerase catalytic domain of Polθ and inhibits MMEJ in a dose-dependent manner, with a cell EC50 of 150 nM
.
At the same time, ART558 also shows a high degree of selectivity and does not inhibit other human DNA polymerases, including Polα, Polγ, Polη and Polν
.
In addition, only ART558 caused radiation sensitivity in Polθ wild-type but not Polθ null mouse embryonic stem cells.
ART615 did not show the same effect; similarly, only ART558 showed sensitivity to BRCA gene mutant cells and verified POLQ The genetic inactivation of BRCA2 confers synthetic lethality to BRCA2 gene defects and resensitization to resistant PARP inhibitors
.

However, ART558 exhibits poor in vitro metabolic stability in rat microsomes; therefore, the Polθ inhibitor ART812, which has a similar framework and exhibits good bioavailability and low clearance in rat in vivo experiments, is used.
Research on anti-cancer efficacy in tumor xenograft model
.

ART812 structure and anti-cancer activity (source, reference 8)

It can be seen that ART812 shows a powerful single-agent effect in the body, can significantly inhibit tumor growth, and the animal weight change is small, so it can be said to have potential efficacy and safety
.
It is believed that if ART4215 is also the same backbone compound, it will definitely show more excellent preclinical data
.

Summary

With the in-depth research on Polθ, its potential DDR function has gradually attracted attention
.
In particular, the analysis of the structure of Polθ protein can accelerate the research of Polθ inhibitors by means of AI or CADD, which provides strong technical support for the development of small molecule inhibitors
.

Although ART4215 has just announced clinical information, the potential clinical treatment effect is still unclear
.
However, based on multiple in vitro and in vivo studies, especially the continued attention of giants, it can be seen that Polθ also has strong clinical potential, especially in the application of synthetic lethal and PARP resistant tumors
.
In addition, given that there are fewer drugs in the current layout and clinical research, the preclinical research and data disclosed by Artios also provide an important reference, and domestic companies may wish to consider intervention in advance
.

In addition, considering the function of RAD51 in DDR and the early clinical data disclosed by the only clinical drug CYT-0851 at this year's ASCO meeting, it also shows certain monotherapy potential
.
It is possible that RAD51 inhibitors and Polθ inhibitors may also be used in combination, especially in non-BRCA1/BRCA2 mutant tumors, which is expected to further expand the therapeutic areas of the two types of drugs
.

Reference

[1]Bridges, CB, he origin of variations in sexual and sex-limited characters.
Am.
Nat.
, 1922.
56: p.
51-63

[2]Shima N, et al.
Phenotype-based identification of mouse chromosome instability mutants.
Genetics 2003.
163.
1031–1040

[3]Seki M, et al.
POLQ (Pol theta), a DNA polymerase and DNA-dependent ATPase in human cells.
Nucleic Acids Res.
2003.
31.
6117–6126

[4]Samuel J Black, et al.
DNA Polymerase θ: A Unique Multifunctional End-Joining Machine.
Genes 2016.
7.
67

[5]Alessandra Brambati,et al.
DNA polymerase theta (Polu) – an error-prone polymerase necessary for genome stability.
Current Opinion in Genetics & Development 2020.
60:119–126

[6]Jia Zhou, et al.
A first-in-class polymerase theta inhibitor selectively targets homologous-recombinationdeficient tumors.
Nature Cancer,2021:598–610

[7]Gurushankar Chandramouly, et al.
Pol θ reverse transcribes RNA and promotes

RNA-templated DNA repair.
Chandramouly et al.
, Sci.
Adv.
2021; 7: eabf1771

[8]Diana Zatreanu, et al.
Polθ inhibitors elicit BRCA-gene synthetic lethality

and target PARP inhibitor resistance.
NATURE COMMUNICATIONS | (2021) 12:3636

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