P1, N=130, Not yet recruiting, Jiangsu Simcere Pharmaceutical Co., Ltd.

P1, N=30, Not yet recruiting, Hangzhou SynRx Therapeutics Biomedical Technology Co., Ltd

Polθ inhibitors enhanced the anti-leukemic effects of mainstream drugs such as FLT3 kinase inhibitor quizartinib, cytarabine and etoposide in vitro and in mice with FLT3(ITD);DNMT3Amut leukemia. Altogether, Polθ is an attractive target in DNMT3Amut hematological malignancies.

To improve CFTR cDNA insertion in human airway basal stem cells (ABCs), we evaluated the use of the small molecules AZD7648 and ART558, which inhibit non-homologous end-joining (NHEJ) and micro-homology mediated end-joining (MMEJ). Adding AZD7648 did not increase off-target editing. Further studies are necessary to validate if AZD7648 treatment enriches cells with oncogenic mutations.

In our studies we hypothesized that inhibition of DNA polymerase theta (Polθ) and its combination with Poly (ADP-ribose) polymerase 1 (PARP1) or RAD52 inhibition and the alkylating drug temozolomide (TMZ) has an anticancer effect on glioblastoma cells (GBM21), whereas it has a low impact on normal human astrocytes (NHA). The impact on normal cells is much lower, especially when considering cell viability and DNA damage. In conclusion, we would like to highlight that Polθ inhibition used in combination with PARP1 or RAD52 inhibition has great potential to kill glioblastoma cells, and shows a synthetic lethal effect, while sparing normal astrocytes.

To improve CFTR cDNA insertion in human airway basal stem cells (ABCs), we evaluated the use of the small molecules AZD7648 and ART558 which inhibit non-homologous end joining (NHEJ) and micro-homology mediated end joining (MMEJ). Adding AZD7648 did not increase off-target editing. Further studies are necessary to validate if AZD7648 treatment enriches cells with oncogenic mutations.

P1, N=158, Recruiting, MOMA Therapeutics | Not yet recruiting --> Recruiting

P1, N=52, Not yet recruiting, Repare Therapeutics

P1, N=158, Not yet recruiting, MOMA Therapeutics

These findings suggest that increased POLQ expression could serve as a valuable clinical marker and a potential therapeutic target in the treatment of thyroid cancer.

P1, N=390, Active, not recruiting, Artios Pharma Ltd | Phase classification: P1/2 --> P1 | Trial completion date: Jan 2026 --> Aug 2025 | Trial primary completion date: Aug 2025 --> Mar 2025

We hope that the screening results and the binding modes are helpful for designing the highly active POLQ polymerase inhibitors and the models of the molecular design workflow can be used as reliable tools for drug design.

P1, N=30, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P1/2, N=135, Recruiting, GlaxoSmithKline | Trial completion date: Nov 2025 --> Nov 2029 | Trial primary completion date: Jun 2025 --> Dec 2027

Moreover, the combination of POLQ inhibitor and ferroptosis inducer synergistically suppressed MGC-803 xenograft tumor growth and diminished metastasis. Our results identify a POLQ-mediated stemness and ferroptosis defense mechanism and provide a new therapeutic strategy for gastric cancer.

Cells were pretreated with simvastatin or lovastatin before GSK101...Herein, we showed that statins can modulate gliosis and TNF-α expression in Müller cells, protecting RGCs. These data further support the neuroprotective effect of statins, promoting them as a potential treatment for glaucoma.

P1/2, N=390, Active, not recruiting, Artios Pharma Ltd | Recruiting --> Active, not recruiting | Trial completion date: Aug 2025 --> Jan 2026 | Trial primary completion date: Mar 2025 --> Aug 2025

P1/2, N=135, Recruiting, GlaxoSmithKline | Phase classification: P1 --> P1/2

P1, N=30, Suspended, National Cancer Institute (NCI) | Initiation date: Oct 2023 --> Jul 2023

Thus, DNA/chromatin binding and TMEJ activity of PolΘ were restored upon PARG-mediated removal of PAR repressive marks on PolΘ. This process seems to play a critical role in protecting OTK-positive hematopoietic malignant cells from genotoxic effect of formaldehyde generated by altered serine/one-carbon cycle metabolism.

P1, N=112, Recruiting, GlaxoSmithKline | Not yet recruiting --> Recruiting | Phase classification: P1/2 --> P1

DNMT3A mutations promote resistance to anthracyclines (including daunorubicin, the component of standard "7+3" induction therapy), interferon alpha, and ABL1 kinase inhibitor imatinib...The combination of Polθis + quizartinib and Polθis + etoposide completely eradicated clonogenic activity of these cells while Polθis + cytarabine and Polθis + azacytidine exerted modest and weak effects, respectively, when compared to individual compound treatments...Median survival time of the mice will be recorded. Altogether, we discovered that Polθ protects OTK-positive DNMT3A-deficient myeloid malignant cells from the toxic effects of DSBs and identified Polθ as a novel therapeutic target.

P1/2, N=112, Not yet recruiting, GlaxoSmithKline

P1, N=30, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1, N=30, Recruiting, National Cancer Institute (NCI) | Initiation date: Jul 2023 --> Oct 2023

P1/2, N=250, Recruiting, Artios Pharma Ltd | Not yet recruiting --> Recruiting

P1, N=30, Recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2023 --> Jul 2023

Small molecule inhibitor of Poltheta (Polthetai) when combined with PARP or RAD52 inhibitors (PARPi, RAD52i) caused accumulation of DSBs and exerted increased effect against HR-deficient leukemia and myeloproliferative neoplasm cells. Implications: In conclusion, we show that PARPi or RAD52i might improve therapeutic effect of Polthetai against HR-deficient leukemias.

P1/2, N=250, Not yet recruiting, Artios Pharma Ltd

Overall, POLQ, a key mediator in the MMEJ pathway, is critical for DSB repair in BRCA2-deficient PDAC. Its inhibition represents a synthetic lethal approach to block tumor growth while simultaneously stimulating an immune response.

P1, N=30, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

Depletion of CD8 T cells compromised the efficacy of POLθ inhibition, whereas antitumor effects were augmented in combination with anti-PD-1 immunotherapy. Collectively, our findings demonstrate that POLθ inhibition induces immune responses in a cGAS/STING-dependent manner and provide a rationale for combining POLθ inhibition with immune checkpoint blockade for the treatment of HR-deficient cancers.

In vitro, single-agent treatment with novobiocin or ART558 caused a significant cytotoxic effect at physiologically relevant concentrations in ATM-deficient cells and co-treatment of novobiocin or ART558 with AZD0156 was synergistic in killing ATM-proficient MCL cells. Importantly, POLQ inhibitors significantly decreased the cell viability of MCIR1, which is an ibrutinib-resistant MCL cell line... POLQ is a promising target in MCL, especially in ATM-deficient setting. In ATM-proficient MCL, targeting ATM and POLQ is synergistic. Our data has the potential to uncover novel biomarker-driven drug therapy of POLQ inhibitors in R/R MCL.

P1/2, N=290, Recruiting, Artios Pharma Ltd | N=206 --> 290

P1, N=30, Not yet recruiting, National Cancer Institute (NCI)

Genetic knockdown of POLQ or pharmacological inhibition by NVB decreased radioresistance in lung adenocarcinoma while causing little toxicity to normal pulmonary epithelial cells. In conclusion, POLQ is a promising and practical cancer-specific target to impair tumorigenesis and enhance radiosensitivity in NSCLC.

Moreover, OTK inhibitor or DPC-inducing drug etoposide enhanced anti-leukemia effect of POLq inhibitor (POLqi) in vitro and in vivo. In conclusion, we demonstrated that POLq plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde and that it can be targeted to achieve therapeutic effect.

While the MRN complex nucleolytically processes ssDNA gaps, CDK6 promotes cell-cycle progression, thereby exacerbating replication stress, a feature of BRCA1-deficient cells that lack POLθ activity. Thus, ssDNA gap formation, modulated by cell-cycle regulators and MRN complex activity, underlies the synthetic lethality between POLθ and BRCA1, an important insight for clinical trials with POLθ inhibitors.

Moreover, OTK inhibitor or DPC-inducing drug etoposide enhanced anti-leukemia effect of POLθ inhibitor (POLθi) in vitro and in vivo...A scheme illustrating functional pathway where OTKs - reprogrammed serine/1C cycle – produced formaldehyde induces DPCs which are likely repaired by POLθ-mediated end-joining (TMEJ). OTKs also enhance the expression of POLθ by stimulating ERK1/2 serine/threonine kinases, which inhibit c-CBL E3 ligase-dependent ubiquitination of POLθ and its proteasomal degradation.

As previously reported, we recently identified the first selective small molecule Polθ in vitro probe, 22 (ART558), which recapitulates the phenotype of Polθ loss, and in vivo probe, 43 (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo...The crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a "closed" enzyme conformation. Additionally, the structural biology platform provided a basis for rational optimization based primarily on reduced ligand conformational flexibility.

Peposertib is an inhibitor of DNA-dependent protein kinase (DNA-PK), which is a key driver of nonhomologous end-joining (NHEJ)...Consequently, the combination of peposertib plus novobiocin resulted in synthetic lethality in TP53-deficient tumor cell lines, organoid cultures, and patient-derived xenograft models. Thus, the combination of a targeted DNA-PK/NHEJ inhibitor with a targeted POLθ/MMEJ inhibitor may provide a rational treatment strategy for TP53-mutant solid tumors.