AZD0156

To overcome these hurdles, we developed a bone-targeted, glutathione (GSH)-responsive polymeric nanoparticle (NPALN/Mn-AP) that chelates manganese (Mn) and delivers an ATM inhibitor (AZD0156) and a PRMT5 inhibitor (GSK3326595). By functionalizing this nanoplatform with alendronate (ALN) into NPALN/Mn-AP, we achieve preferential accumulation in bone tumors...In vivo studies demonstrate that NPALN/Mn-AP significantly inhibits OS progression and boosts systemic immune responses. This dual-action, bone-specific nanotherapeutic platform synchronized DNA-repair inhibition and Mn-enhanced immune-stimulation, offering a promising new approach for effective osteosarcoma treatment.

Natural killer cells showed only a limited contribution to the killing of HNSCC cells pretreated with RT or RT + DDRi. However, a subset of patients with head and neck tumors-such as those represented by the HSC4 model-might still benefit from combining RT with ATMi rather than ATRi to enhance NK cell-mediated tumor killing.

In xenograft models, AZD0156 combined with cisplatin substantially suppressed tumor growth compared to monotherapy, with acceptable tolerability profiles. These findings identify ATM inhibition as a promising strategy to overcome gemcitabine resistance in CCA, particularly in tumors with compromised alt-NHEJ repair capacity, providing a mechanistic rationale for clinical development of this combination therapy.

Finally, the combination of radiotherapy and ACPP-AZD0156 potentiated immune checkpoint inhibitors that resulted in durable tumor control. The therapeutic synergies of ACPP targeted ATM inhibitor to radiosensitize and stimulate anti-tumor immune responses provides a rationale for developing tumor-targeted radiosensitizer drug conjugates that restrict radiosensitization to cancer cells that then engages anti-tumor immune responses to improve cancer patient outcomes.

Inhibitors such as KU-55933, KU-60019, and AZD1390 have shown the potential to sensitize cancer cells to radiotherapy by impairing DNA repair, thereby enhancing treatment efficacy...Currently, none have gained approval from the FDA or EMA, but six candidates, AZD1390, AZD0156, ZN-B-2262, SYH2051, WSD0628 and M3541 are in clinical trials, often as adjuncts to radiotherapy or in combination with PARP inhibitors. Their safety and effectiveness, however, are still under investigation. This review synthesizes ATM's dual roles and the therapeutic promise of targeting ATM in cancer radiotherapy.

We used AZD0156, an ATM inhibitor, and VE-822, an ATR inhibitor, in combination with normo-fractionated RT to treat two HPV-positive and two HPV-negative HNSCC cell lines. In co-culture with NK cells, an upregulation of activation markers on NK cells was observed, particularly after contact with RT + ATMi-treated HPV-negative HNSCC cells. We conclude that ATM inhibitor-related induction of senescence in HNSCC cells shapes the tumor micro-environment in way that NK cell phenotype is changed.

Two phosphatase inhibitors, staurosporine and AZD0156, inhibit epithelial-to-mesenchymal transition (EMT) in cholangiocarcinoma cells by suppressing TET1 expression. In conclusion, it is also demonstrated that PPM1G can be employed as a therapeutic target to impede the progression of CCA by catalyzing the dephosphorylation of TET1, which diminishes the capacity of TET1 to target the CLDN3 promoter to activate transcription and inhibit EMT in CCA.

The toxic and immunogenic effects of the smKI AZD0156 (ATMi) and VE-822 (ATRi) in combination with a hypo-fractionated scheme of 2x5Gy RT on HPV-negative (HSC4, Cal-33) and HPV-positive (UM-SCC-47, UD-SCC-2) HNSCC cell lines were analyzed as follows: cell death (necrosis, apoptosis; detected by AnxV/PI), expression of immunostimulatory (ICOS-L, OX40-L, TNFSFR9, CD70) and immunosuppressive (PD-L1, PD-L2, HVEM) checkpoint marker using flow cytometry; the release of cytokines using multiplex ELISA and the gene expression of Cal-33 on mRNA level 48 h post-RT. This includes pro-inflammatory signaling induced by RT + ATRi but also anti-inflammatory signals. These findings were confirmed by RNAseq analysis, which further highlighted the immune-suppressive nature of RT + ATMi.

Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacological inhibition of ATM enhanced the efficacy of PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy.

SLFN11 is frequently methylated in human ESCC. Methylation of SLFN11 is sensitive marker of ATM inhibitor in ESCC.

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.

A radiosensitizing effect can be confirmed after treatment with AZD0156, Afatinib or Alpelisib in three organoid lines using this assay so far. Establishment of HNSCC organoids was successful using our workflow. These 3D models can be used to screen for potential radiosensitizers. For validation, we established an organoid formation assay to determine the clonogenic survival as an important endpoint in radiobiology.