ATR inhib 
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  • ||||||||||  VE-821 / EMD Serono, Vertex, AB-110 / Angiocrine
    Journal:  Pharmacological degradation of ATR induces antiproliferative DNA replication stress in leukemic cells. (Pubmed Central) -  Mar 23, 2024   
    It is derived from the ATR inhibitor VE-821 and recruits the E3 ubiquitin-ligase component cereblon to ATR...This mechanism provokes DNA replication catastrophe and augments anti-leukemic effects of the clinically used ribonucleotide reductase-2 inhibitor hydroxyurea...Treatment of wild-type but not of cereblon knockout cells with Abd110 stalls their proliferation which verifies that ATR elimination is the primary mechanism of Abd110. Altogether, our findings demonstrate specific anti-leukemic effects of an ATR PROTAC.
  • ||||||||||  Journal:  AKTing on R Loops Makes for an ATRactive Target in Ovarian Cancer Therapy. (Pubmed Central) -  Mar 19, 2024   
    The work by Huang and colleagues thus provides compelling rationale for the exploration of combined targeting of the AKT and ATR pathways as a potentially broadly applicable treatment of advanced HGSOC. See related article by Huang et al., p. 887.
  • ||||||||||  Journal, BRCA Biomarker, PARP Biomarker:  AKT1 interacts with DHX9 to mitigate R-loop-induced replication stress in ovarian cancer. (Pubmed Central) -  Mar 18, 2024   
    Moreover, DHX9 was upregulated in tumors from PARPi-resistant BRCAm HGSOC patients, and high co-expression of DHX9 and AKT1 correlated with worse survival. Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R-loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status.
  • ||||||||||  elimusertib (BAY 1895344) / Bayer
    Preclinical, Journal:  Preclinical Evaluation of the ATR inhibitor BAY 1895344 as a Radiosensitizer for Head and Neck Squamous Cell Carcinoma. (Pubmed Central) -  Mar 18, 2024   
    Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R-loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status. These findings demonstrated that BAY 1895344 increased in vitro and in vivo radiosensitivity in HPV-negative HNSCC preclinical models, suggesting therapeutic potential warranting evaluation in clinical trials for patients with locally advanced or recurrent HPV-negative HNSCC.
  • ||||||||||  Journal:  Functionally-instructed modifiers of response to ATR inhibition in experimental glioma. (Pubmed Central) -  Mar 17, 2024   
    These findings demonstrated that BAY 1895344 increased in vitro and in vivo radiosensitivity in HPV-negative HNSCC preclinical models, suggesting therapeutic potential warranting evaluation in clinical trials for patients with locally advanced or recurrent HPV-negative HNSCC. In conclusion, our study leads to the identification of novel combination therapies involving ATRi that could inform future preclinical studies and early phase clinical trials.
  • ||||||||||  ceralasertib (AZD6738) / AstraZeneca
    Review, Journal, Tumor mutational burden:  Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes. (Pubmed Central) -  Mar 17, 2024   
    In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system, and their interplay and, therefore, potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.
  • ||||||||||  5-fluorouracil / Generic mfg.
    Journal:  Tumor acidosis-induced DNA damage response and tetraploidy enhance sensitivity to ATM and ATR inhibitors. (Pubmed Central) -  Mar 14, 2024   
    The efficacy of a combination of these drugs with 5-FU is further documented in 3D spheroids as well as in patient-derived colorectal tumor organoids. These data position tumor acidosis as a revelator of the therapeutic potential of DNA repair blockers and as an attractive clinical biomarker to predict the response to a combination with chemotherapy.
  • ||||||||||  berzosertib (M6620) / EMD Serono
    Non-linear IV pharmacokinetics of the ATR inhibitor berzosertib (M6620) in mice (Section 24) -  Mar 5, 2024 - Abstract #AACR2024AACR_9377;    
    Increased doses of berzosertib were associated with greater than proportional increases in plasma and tissue exposure most likely due to saturation of plasma protein binding. Our results will help to understand preclinical pharmacodynamic and toxicity data and subsequent PBPK modeling to inform optimal dosing and clinical deployment of berzosertib.
  • ||||||||||  DNA polymerase beta expression in head & neck cancer modulates the poly-ADP-ribose-mediated replication checkpoint (Section 22) -  Mar 5, 2024 - Abstract #AACR2024AACR_9358;    
    In conclusion, our findings propose a novel therapeutic paradigm for HNSCC, employing combination therapy with ATR or CHK1 inhibitors and PARG inhibitors. This approach offers a targeted strategy, presenting a promising avenue for the development of more effective and less toxic treatment modalities in the management of HNSCC and may help overcome resistance from elevated expression of Pol?.
  • ||||||||||  ceralasertib (AZD6738) / AstraZeneca, BOLD-100 / Bold Therap
    Co-downregulation of GRP78 and ATR enhances apoptosis in pancreatic ductal adenocarcinoma (Section 16) -  Mar 5, 2024 - Abstract #AACR2024AACR_2892;    
    GRP78 could serve as one of the potential therapeutic targets in PDAC. The combination of BOLD-100 and AZD6738 demonstrates a synergistic effect suggesting GRP78/ATR dual targeting as a promising therapeutic option for patients with PDAC.
  • ||||||||||  onvansertib (PCM-075) / Cardiff Oncology
    The PLK1 inhibitor, onvansertib, synergizes with paclitaxel in small cell lung cancer (Section 25) -  Mar 5, 2024 - Abstract #AACR2024AACR_2726;    
    P2
    The PLK1 inhibitor onvansertib in combination with paclitaxel showed synergy in multiple SCLC cell lines in vitro and potent anti-tumor activity in cisplatin-sensitive and -resistant SCLC PDX models in vivo. Tumor tissue analysis is underway to detail the mechanisms of this interaction.
  • ||||||||||  elimusertib (BAY 1895344) / Bayer
    Preclinical, Journal:  The ATR inhibition by Elimusertib enhances the radiosensitivity of MDA-MB-231 triple negative breast cancer in vitro. (Pubmed Central) -  Feb 29, 2024   
    ATR inhibition by Elimusertib in combination with RT may be a promising new treatment strategy in the treatment of TNBC. However, further experiments should be performed to elucidate the underlying molecular mechanisms of the therapeutic efficacy of this combination treatment and its association with DNS repair mechanisms in TNBC, in vitro and in vivo.
  • ||||||||||  ART0380 / Artios Pharma
    Journal:  Ataxia-Telangiectasia Mutated (ATM) loss of function displays variant and tissue-specific differences across tumor types. (Pubmed Central) -  Feb 28, 2024   
    However, further experiments should be performed to elucidate the underlying molecular mechanisms of the therapeutic efficacy of this combination treatment and its association with DNS repair mechanisms in TNBC, in vitro and in vivo. These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.
  • ||||||||||  camonsertib (RP-3500) / Repare Therap
    Journal:  Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500). (Pubmed Central) -  Feb 23, 2024   
    P1, P1/2,
    Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.
  • ||||||||||  Review, Journal:  Targeting ATR in patients with cancer. (Pubmed Central) -  Feb 21, 2024   
    Key challenges that remain in the clinical development of ATR inhibitors include the optimization of their therapeutic index and the development of rational combinations with these agents. In this Review, we detail the molecular mechanisms regulated by ATR and their clinical relevance, and discuss the challenges that must be addressed to extend the benefit of ATR inhibitors to a broad population of patients with cancer.
  • ||||||||||  Journal, PARP Biomarker:  APOBEC3A induces DNA gaps through PRIMPOL and confers gap-associated therapeutic vulnerability. (Pubmed Central) -  Jan 23, 2024   
    When used in combination, PARP and ATR inhibitors selectively kill A3A-expressing cells synergistically in a manner dependent on PrimPol-generated gaps. Thus, A3A-induced replication stress arises from PrimPol-generated ssDNA gaps, which confer a therapeutic vulnerability to gap-targeted DNA repair inhibitors.
  • ||||||||||  ceralasertib (AZD6738) / AstraZeneca
    Journal:  Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation. (Pubmed Central) -  Jan 17, 2024   
    P1
    Overall, this study identifies ATR inhibition as a strategy to enhance the DNA-damaging ability of glioblastoma standard treatment, while providing preliminary evidence that ATR inhibition induces an innate immune gene signature that warrants further investigation. Ceralasertib monotherapy was tolerated at 160 mg BD intermittent and associated with anti-tumor activity.