Power target Polθ: the potential to burst into the game

Article source: Medical Rubik's Cube Pro

Author: Leaf

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 research

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)

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

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].

In 2003, Shima N et al.

Schematic diagram of Polθ[4]

Mammalian cells have evolved a variety of ways to repair DNA double-strand breaks (DSB) to ensure genome stability

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)

Source: Reference 6

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

ART4215 : Potential burst out, 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

Novartis is also another pharmaceutical giant focusing on DDR besides GSK

Although ART4215 currently has less public information; however, Artios published preclinical data and research status of selective small molecule Polθ polymerase inhibitors on Nature Communications in June this year [8]

Unlike Ideala, Artios disclosed in this article a class of highly active and selective small molecule Polθ polymerase allosteric 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

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 rate in rat in vivo experiments, is used.

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

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

Summarize

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