AZD1390

These findings indicate that DNA damage response inhibitors can enhance IFN signaling following X-, proton and carbon ion irradiation, with a strong positive dependency on LET.

P1, N=180, Recruiting, AstraZeneca | N=120 --> 180 | Trial completion date: Apr 2026 --> Sep 2026 | Trial primary completion date: Apr 2026 --> Sep 2026

Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR and MMEJ activity, suggesting that these pathways contribute to treatment resistance. We further show that a combination of G2/M checkpoint deficiency and reliance upon ATM-dependent DSBR renders TP53 mutant GBMs hypersensitive to TMZ/AZD1390 and radiation/AZD1390 combinations. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes an approach for simultaneously measuring multiple DSBR pathways in treatment selection and oncology research.

Using inhibitors targeting ATM (AZD1390), ATR (AZD6738) and DNA-Pkcs (AZD7648), we observed that this led to significantly decreased clonogenic survival of HNSCC cell lines following both X-ray and proton irradiation. We confirmed that the inhibitors in combination with X-rays and protons led to DSB persistence, and increased micronuclei formation. Cumulatively, our data suggest that targeting DSB repair, particularly via ATM and DNA-Pkcs inhibition, can exacerbate the impact of ionising radiation in sensitising HNSCC cell models.

P1, N=30, Recruiting, The Netherlands Cancer Institute | N=15 --> 30 | Trial completion date: Mar 2024 --> Jul 2028 | Trial primary completion date: Mar 2024 --> Mar 2026

P1, N=120, Recruiting, AstraZeneca | Trial completion date: Feb 2025 --> Apr 2026 | Trial primary completion date: Feb 2025 --> Apr 2026

P1, N=37, Recruiting, Nader Sanai | Trial primary completion date: Jan 2024 --> Jul 2024

Molecular docking and dynamic simulation analyses highlight strong binding affinities of quercetin for Y2080D and AZD0156 for C2770G, suggesting potential therapeutic options...The study underscores the significance of Y2080D and C2770G mutations, offering valuable insights for future precision medicine targeting-specific ATM. Despite informative computational analyses, a significant research gap exists, necessitating essential in vitro and in vivo studies to validate the predicted effects of ATM mutations on protein structure and function.

P1, N=200, Recruiting, University of Leeds | Trial completion date: May 2027 --> Mar 2028 | Trial primary completion date: Mar 2023 --> Apr 2025

We evaluated the effects of AZD1390 or a structurally related compound AZD0156 on innate immune signaling and found that both inhibitors enhanced radiation-induced T1IFN expression via the POLIII/RIG-I/MAVS pathway. Adaptive immune responses to combination therapy provided systemic control of contralateral tumors outside of the radiation field. Taken together, we show that a clinical candidate ATM inhibitor enhances radiation-induced T1IFN leading to both innate and subsequent adaptive anti-tumoral immune responses and sensitization of otherwise resistant pancreatic cancer to immunotherapy.

Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53-mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53-mutant cells to ATM inhibitor-mediated radiosensitization.

P1, N=120, Recruiting, AstraZeneca | Trial completion date: Dec 2026 --> Feb 2025 | Trial primary completion date: Dec 2026 --> Feb 2025

Starting from clinical candidate AZD0156, 4, we investigated the imidazoquinolin-2-one scaffold with the goal of improving likely CNS exposure in humans. These studies identified compound 24 (AZD1390) as an exceptionally potent and selective inhibitor of ATM with a good preclinical pharmacokinetic profile. 24 showed an absence of human transporter efflux in MDCKII-MDR1-BCRP studies (efflux ratio <2), significant BBB penetrance in nonhuman primate PET studies (K 0.33) and was deemed suitable for development as a clinical candidate to explore the radiosensitizing effects of ATM in intracranial malignancies.

The five AML cell lines demonstrated sensitivity to monotherapy with GSK-368, AZD-1390, or AZD-6738 (EC50 value ranges from 5.461 to 7.349 nM, 5.821 to 10.120 nM, and 7.618 to 10.100 nM, respectively). DNMT1, ATM, and ATR possess potential as therapeutic targets for AML. Both individual targeting and combination targeting of these molecules have been confirmed as promising therapeutic approaches for AML.

P1, N=120, Recruiting, AstraZeneca | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2026

Our results demonstrate that AZD1390 effectively sensitizes breast cancer CNS metastasis to radiation therapy in DDR mutant tumors. This study demonstrates the potential of using AZD1390 as a novel therapeutic agent for patients with breast cancer CNS metastasis.

The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were combined with varied inhibitors of DNA damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated; AZD-1390), ATR (ataxia telangiectasia and Rad3-related protein; berzosertib or elimusertib), and DNA-PK (DNA-dependent protein kinase; nedisertib or VX-984). The potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways was assessed in multicellular tumor spheroids. Although most combinations demonstrated additive cytotoxicity, synergistic cytotoxicity was observed for several drug combinations.

P1, N=120, Recruiting, AstraZeneca | Trial completion date: Sep 2024 --> Dec 2024 | Trial primary completion date: Sep 2024 --> Dec 2024

More importantly, 10q exhibited good liver microsomes stability in different species and also showed moderate inhibitory activity against HT-29 cells in combination treatment with the ATM inhibitor AZD1390. Thus, this work provides a promising lead compound against ATR for further study.

P1, N=48, Recruiting, Memorial Sloan Kettering Cancer Center | Not yet recruiting --> Recruiting | Trial completion date: Mar 2025 --> May 2028 | Trial primary completion date: Mar 2025 --> May 2028

Material and Methods Eight patient derived PDAC cell lines were treated with small molecule inhibitors of ATR (AZD6738 : 20nM - 1µM), PARP (olaparib : 20nM - 1µM) or ATM (AZD1390: 1nM - 100nM) alone and in combination with radiation (0 to 6 Gy). Figure 1 : Survival curves showing radiosensitization of  7 patient derived PDAC cell lines with ATRi(green), ATMi(Blue), PARPi(Red) Figure 2 : Correlation between Replication stress Score and Homologous recombination repair deficiency with ATRi/ATMi  and PARPi radiosensitization Conclusion DDR inhibitors radiosensitized PDAC with the magnitude of radiosensitization depending on Replication Stress and DDR deficiency. These data provide potential therapeutic strategies in the radioresistance setting.

The primary objective is to assess safety and determine the recommended phase II dose of each DDRi+RT combination. As of 06/01/2023, CONCORDE-A (olaparib) and CONCORDE-B (AZD1390) are open to recruitment across 9 centres. The trial continues to recruit and CONCORDE-C (RT±ceralasertib with consolidation durvalumab±ceralasertib) has been approved and is due to open in January 2023. Two further study arms are planned. A parallel multimodality translational program to identify biomarkers of treatment response, toxicity and the impact on the immune system are in development.

Our study supports the clinical evaluation of AZD1390 in combination with radiation in pediatric patients with HGG.

Combination of Gal-9 inhibition with AZD1390, a selective ATM inhibitor currently evaluated in clinical trials, significantly suppressed tumor growth and prolonged survival in multiple syngeneic mouse models, including the poorly-immunogenic LLC lung tumors that do not respond to PD-1/PD-L1 blockade, concomitant with increased T cell infiltration. These results reveal Gal-9 induction via STING/IFNβ signaling as an important mechanism mediating tumor immune escape that could be targeted for cancer immunotherapies, and unveil a novel anti-Gal-9-based combination strategy for cancer immunotherapies in a wide variety of malignancies, including those resistant to PD-1/PD-L1 blockade.

P1, N=120, Recruiting, AstraZeneca | Trial completion date: May 2024 --> Aug 2024 | Trial primary completion date: May 2024 --> Aug 2024

PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.

These results suggest that AZD6738, AZD1775, and AZD1390 all potentiate T-DXd activity in vitro and in vivo, and the combination interactions with AZD6738 and AZD1775 were much stronger in some tumor models over bone marrow cells in vitro. These data suggest further investigation of these combinations in clinical studies may be warranted.

P1, N=120, Recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

The cellular stress induced by Temozolomide (TMZ) increases innate immune ligands, which could be exploited to promote immune recognition...To further promote immune recognition, we sought to augment the TMZ-induced stress response by exploring the combination of DNA alkylation with either PARP (Niraparib) or ATM Kinase inhibition (AZD1390)...We are currently determining whether these combinatorial treatments improve gamma delta T-cell cytotoxicity against GBM cells and in vivo tumor models. Taken together, our data suggest that enhancing cell stress responses induced by chemotherapies may permit novel immunotherapy therapeutic interventions for brain tumor patients.

We show that the combination treatment of the EZH2 inhibitor GSK126 and the ATM inhibitor AZD1390 led to reduced colony formation, increased genotoxic stress and apoptosis-mediated cell death in BRCA1-deficient mammary tumor cells in vitro. These findings were corroborated by in vivo experiments, showing that simultaneous inhibition of EZH2 and ATM significantly increased anti-tumor activity in mice bearing BRCA1-deficient mammary tumors. e28 Conclusion Taken together, we identified a synthetic lethal interaction bet- ween EZH2 and ATM and suggest considering the synergistic interaction bet- ween EZH2 and ATM as novel molecular combination for the treatment of BRCA1-mutant breast cancer.

Results and Discussions Our drug screen identifies several drugs with potential synergy with PARP inhibitor Rucaparib, including cisplatin and ATM inhibitor AZD1390. On the contrary, targeting Alt-EJ and HR in p53 null tumors forces cells to rely on NEHJ which ultimately leads to unsustained instability and cell death.Conclusion The inhibition of ATM and PARP causes a synthetic lethal context leading to cancer cell death in TP53 deficiency. This is of utmost importance as loss of function alterations in p53 have been reported in up to 50% mCRPCs, suggesting that the therapeutic landscape for PARPi is likely to expand in combination with other DDR pathway inhibitors.

Results and Discussions Our drug screen identifies several drugs with potential synergy with PARP inhibitor Rucaparib, including cisplatin and ATM inhibitor AZD1390. On the contrary, targeting Alt-EJ and HR in p53 null tumors forces cells to rely on NEHJ which ultimately leads to unsustained instability and cell death.Conclusion The inhibition of ATM and PARP causes a synthetic lethal context leading to cancer cell death in TP53 deficiency. This is of utmost importance as loss of function alterations in p53 have been reported in up to 50% mCRPCs, suggesting that the therapeutic landscape for PARPi is likely to expand in combination with other DDR pathway inhibitors.

Results and Discussions Our drug screen identifies several drugs with potential synergy with PARP inhibitor Rucaparib, including cisplatin and ATM inhibitor AZD1390. On the contrary, targeting Alt-EJ and HR in p53 null tumors forces cells to rely on NEHJ which ultimately leads to unsustained instability and cell death.Conclusion The inhibition of ATM and PARP causes a synthetic lethal context leading to cancer cell death in TP53 deficiency. This is of utmost importance as loss of function alterations in p53 have been reported in up to 50% mCRPCs, suggesting that the therapeutic landscape for PARPi is likely to expand in combination with other DDR pathway inhibitors.

Results and Discussions Our drug screen identifies several drugs with potential synergy with PARP inhibitor Rucaparib, including cisplatin and ATM inhibitor AZD1390. On the contrary, targeting Alt-EJ and HR in p53 null tumors forces cells to rely on NEHJ which ultimately leads to unsustained instability and cell death.Conclusion The inhibition of ATM and PARP causes a synthetic lethal context leading to cancer cell death in TP53 deficiency. This is of utmost importance as loss of function alterations in p53 have been reported in up to 50% mCRPCs, suggesting that the therapeutic landscape for PARPi is likely to expand in combination with other DDR pathway inhibitors.

P1, N=132, Recruiting, AstraZeneca | Trial completion date: Feb 2023 --> Nov 2023 | Trial primary completion date: Feb 2023 --> Nov 2023

P1, N=132, Recruiting, AstraZeneca | Trial completion date: Jul 2022 --> Feb 2023 | Trial primary completion date: Jul 2022 --> Feb 2023

P1, N=132, Recruiting, AstraZeneca | N=100 --> 132