elimusertib (BAY 1895344) / Bayer - LARVOL DELTA

Targeting ATR to overcome cisplatin resistance in hepatoblastoma. (PubMed, J Hepatol) - "ATR mediates cisplatin resistance in HB. The combination of elimusertib and cisplatin demonstrated preclinical efficacy across patient-derived cultures and multiple in vivo HB models, supporting its potential as a promising therapy for cisplatin-resistant HB."

Journal • Hepatoblastoma • Hepatocellular Cancer • Liver Cancer • Oncology • Pediatrics • Solid Tumor

IDENTIFICATION OF A DNA REPAIR INHIBITOR FOR THE COMBINATION WITH LURBINECTEDIN AND RADIOTHERAPY IN SARCOMA CELL LINES (CTOS 2025) - "Objective: Improved multimodal treatment could optimize therapeutic outcomes for sarcoma patients. Our preclinical data suggest that the combination of LU with RT has no sensitizing effect compared to LU treatment alone in sarcoma cell lines. However, combining LU and IR with DNA repair inhibitors such as the ATRi VE-822 is a promising way to improve sarcoma treatment."

Preclinical • Fibrosarcoma • Liposarcoma • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • Synovial Sarcoma • ANXA5

Differential Response to ATR/Chk1 Inhibition in Preleukemia and Transformed Leukemia in an MLL-ENL Model of Leukemogenesis Reflects Enrichment for Myc-Transcriptional Program (ASH 2024) - "We hypothesize that in preleukemia, ATR/Chk1 DNA damage response (DDR) checkpoint activation serves as part of intrinsic anti-cancer barrier, while in leukemia, ATR-dependent signaling is essential for leukemia cell proliferation and survival.We tested the consequences of ATR/Chk1 inhibition during Mll-ENL leukemogenesis, using ceralasertib (ATRi1, p.o. 25 mg/kg), elimusertib (ATRi2, p.o. 50 mg/kg) and AZD-7762 (Chk1i, i.v. 25 mg/kg), 3-5 times weekly, 1-6 months, using the preleukemic mice...In vitro, MEER cells showed high sensitivity to JAK2i ruxolitinib (RX, IC50 24 nM), higher than to the tested FLT3i...In preleukemia, attenuation of ATR/Chk1 checkpoint promotes the development of leukemia from preleukemia. Combinatory targeting of DDR components and activated oncogenic signaling to induce synthetic lethality in preleukemia stage of MLL remains to be fully elucidated."

Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • AMBRA1 • CHEK2 • FLT3

Dual inhibition of ATR and PARP reverses acquired PARP inhibitor resistance in triple negative breast cancer. (PubMed, Discov Oncol) - "HCC1937 and HCC1937-R Talazoparib (TAL) resistant cells were treated with Elimusertib (ELI) alone as ATR inhibitor (ATRi) and ELI and TAL combination. Therefore, the dual targeting of ATR and PARP is a promising modality to reverse PARPi resistance with the downregulation of ATR-Chk1 based DNA damage response. However, further preclinical and clinical investigations should be required to elucidate the underlying molecular mechanisms behind ATRi and PARPi interactions in TNBC cells."

Journal • Ataxia • Breast Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Triple Negative Breast Cancer • ANXA5 • CHEK1

ATR Inhibitor Elimusertib Suppresses Drug Persister Clones in TP53-Mutated Acute Myeloid Leukemia Via CGAS-Sting-Mediated Cell Death (ASH 2024) - "Among these, the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor elimusertib (BAY1895344) effectively inhibited TP53 mut AML DTPCs at low doses, similar to known inhibitors the CHK1 inhibitor (SRA737) and the Wee1 inhibitor (Adavosertib)...Furthermore, the triple combination treatment of cytarabine, idarubicin, and elimusertib effectively suppressed DTPC formation in TP53 mut AML cell lines...This consequently results in cGAS-STING-mediated cell death following irreparable DNA replication stress accompanied by p53 dysfunction. Our findings provide a basis for developing optimized treatment strategies for patients with TP53-mutant AML using the ATR inhibitor elimusertib."

Acute Myelogenous Leukemia • Ataxia • Hematological Malignancies • Immunology • Leukemia • Movement Disorders • Oncology • Primary Immunodeficiency • CDC25C • CDK1 • CDKN1A • CXCL10 • GNRP • IFI27 • IFIT1 • RSAD2 • SIGLEC1 • STAT1 • STING • TP53

YL0712-3, a Novel ATR/ATM Inhibitor, Demonstrates Anti-Tumor Activity in TP53 Mutant DLBCL through Synthetic Lethality and Degradation of Mutant p53 (ASH 2024) - "The in vitro activity of YL0712-3 was assessed across various TP53 mutant and wild-type DLBCL cell lines, with ATR inhibitor Elimusertib and ATM inhibitor AZD1390 as positive controls. Conclusion : The ATR/ATM inhibitor YL0712-3 effectively targets TP53 mutant DLBCL cells by inhibiting the ATM/Chk2 and ATR/Chk1 pathways and inducing proteasome-mediated degradation of mutant p53 protein. YL0712-3 exhibits promising anti-tumor activity in both in vitro and in vivo models, especially when combined with R-CHOP, presenting a potential therapeutic strategy for TP53 mutant DLBCL."

Synthetic lethality • Ataxia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Immunology • Lymphoma • Movement Disorders • Non-Hodgkin’s Lymphoma • Oncology • Primary Immunodeficiency • Targeted Protein Degradation • CHEK2

TARGETING ATR TO OVERCOME CISPLATIN RESISTANCE IN HEPATOBLASTOMA (SIOP 2025) - "Elimusertib also synergized with other agents, including carboplatin, irinotecan and/or vincristine and demonstrated ability to inhibit mTOR. This study highlights the crucial role of ATR in cisplatin resistance and demonstrates the potent cytotoxic effects of the elimusertib/cisplatin combination in cisplatin-resistant HB models. These findings offer a promising therapeutic option for treating chemoresistant HB."

Hepatoblastoma • Hepatocellular Cancer • Liver Cancer • Pediatrics • Solid Tumor

The ATR inhibitor Elimusertib in Combination with Cisplatin in Patients with Advanced Solid Tumors: a California Cancer Consortium Phase I Trial (NCI10404). (PubMed, Cancer Res Commun) - "Cisplatin combined with elimusertib was associated with hematologic toxicity requiring significant dose de-escalation. Elimusertib PK was consistent with prior studies. Only modest activity was observed. Further clinical evaluation of elimusertib plus cisplatin is not warranted."

Journal • P1 data • Ataxia • Febrile Neutropenia • Hematological Disorders • Immunology • Movement Disorders • Neutropenia • Oncology • Ovarian Cancer • Ovarian Clear Cell Cancer • Primary Immunodeficiency • Solid Tumor • Thrombocytopenia • ATR

HER3 upregulation reduces DS-8201 sensitivity in HER2-positive tumor cells by ATR/CHK1/FoxO1 signaling cascade. (PubMed, Acta Pharmacol Sin) - "Based on this finding, we showed that combining DS-8201 with either a HER3-targeting antibody (SIBP-03) or an ATR inhibitor (BAY1895344) resulted in significant synergistic antitumor efficacy without substantial toxicity in vitro or in vivo. Overall, this study revealed that the ATR/FoxO1/HER3 pathway plays a critical role in modulating the efficacy of DS-8201, suggesting that combining DS-8201 with ATR or HER3 inhibition represents a promising therapeutic strategy for HER2-positive cancers."

Journal • Oncology • CHEK1 • ERBB3 • HER-2

Epigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas. (PubMed, J Clin Invest) - "The Polycomb repressive complex EZH2 inhibitor tazemetostat was recently approved for the treatment of SMARCB1-deficient epithelioid sarcomas, based on the functional antagonism between PRC2 and SMARCB1...We leveraged this collateral synthetic lethal dependency to target PGBD5-dependent DNA damage by inhibition of ATR, but not CHK1, using the ATR inhibitor elimusertib. Consequently, combined EZH2 and ATR inhibition improved therapeutic responses in diverse patient-derived epithelioid and rhabdoid tumors in vivo. This advances a combination epigenetic therapy based on EZH2-PGBD5 synthetic lethal dependency suitable for immediate translation to clinical trials for patients."

Journal • Gene Therapies • Oncology • Rhabdoid Tumor • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • CHEK1 • PGBD5 • SMARCB1

Targeting the DNA damage response prevents regrowth of colorectal peritoneal metastasis-derived organoids following treatment with mitomycin C. (EACR 2025) - "We tested whether inhibitors of the DNA damage response (DDR) could prevent recurrence in an in vitro HIPEC model.Material and Peritoneal metastasis-derived organoids (PMDOs; n=10) were treated with inhibitors of ATR (berzosertib, ceralasertib, elimusertib), CHK1 (rabusertib), and WEE1 (adavosertib) alone, and in combination with MMC, oxaliplatin, or irinotecan. PMDOs can be completely eradicated if MMC treatment is followed by inhibition of ATR or other DDR kinases. DDR inhibitors may, therefore, have value in the adjuvant treatment of peritoneal metastases following CRS-HIPEC."

Colorectal Cancer • Oncology • Solid Tumor • CHEK1

Injectable thermosensitive hydrogel co-loading with ATRi and doxorubicin for the treatment of triple-negative breast cancer. (PubMed, RSC Adv) - "Herein, we developed an injectable thermosensitive hydrogel for localized co-delivery of ATRi-BAY-1895344 (BAY) and doxorubicin (DOX), serving as a localized drug depot to minimize systemic toxicity while ensuring sustained tumor-specific drug release exceeding 4 days. This dual-action strategy overcomes chemo-resistance by disabling DDR compensatory mechanisms and prolongs tumor suppression through controlled drug release. The hydrogel platform represents a functional innovation in localized combination therapy, integrating stimuli-responsive drug delivery with DDR pathway disruption for synergistic efficacy."

Journal • Ataxia • Breast Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • Triple Negative Breast Cancer • ATR

Phase Ib basket expansion trial and alternative-schedule dose-escalation study of ATR inhibitor elimusertib in advanced solid tumors with DNA damage response defects. (PubMed, Cancer Discov) - "There was no association between ATM protein loss or ATM alterations and progression-free survival or overall response. Further studies to define optimal predictive biomarkers for ATR inhibitors as monotherapy and in combination are ongoing."

Journal • P1 data • Breast Cancer • Gynecologic Cancers • Hematological Disorders • Oncology • Solid Tumor • ATM

Testing the Addition of an Anti-cancer Drug, BAY 1895344, to the Usual Chemotherapy Treatment (Cisplatin, or Cisplatin and Gemcitabine) for Advanced Solid Tumors With Emphasis on Urothelial Cancer (clinicaltrials.gov) - P1 | N=74 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2025 ➔ Jun 2026 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Biliary Cancer • Biliary Tract Cancer • Breast Cancer • Cervical Cancer • Cholangiocarcinoma • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Head and Neck Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Penile Cancer • Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer • Urothelial Cancer • ER • HER-2 • PGR

Testing the Addition of an Anti-cancer Drug, Elimusertib (BAY 1895344) ATR Inhibitor, to the Chemotherapy Treatment (Gemcitabine) for Advanced Pancreatic and Ovarian Cancer, and Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial primary completion date: Oct 2024 ➔ Apr 2025

Platinum resistant • Trial primary completion date • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Pancreatic Adenocarcinoma • Pancreatic Cancer • Peritoneal Cancer • Solid Tumor

Comparative in vivo toxicology of ATR inhibitors ceralasertib, elimusertib, and berzosertib alone and in combination with ionizing radiation. (PubMed, Toxicol Appl Pharmacol) - "Cardiotoxicity was observed following single-dose ceralasertib, but no other ATRi, possibly due to high unbound plasma drug concentrations. Our results further support and guide clinical development of ATRi in clinic."

Journal • Preclinical • Ataxia • Cardiovascular • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency

Testing the Addition of an Anti-cancer Drug, Elimusertib (BAY 1895344) ATR Inhibitor, to the Chemotherapy Treatment (Gemcitabine) for Advanced Pancreatic and Ovarian Cancer, and Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | N=64 ➔ 14 | Trial completion date: Feb 2025 ➔ May 2026 | Trial primary completion date: Feb 2025 ➔ Oct 2024

Enrollment change • Trial completion date • Trial primary completion date • Fallopian Tube Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Pancreatic Adenocarcinoma • Pancreatic Cancer • Peritoneal Cancer • Solid Tumor

YF550 is a potent and selective inhibitor of KIF18A, specifically targeting CIN+ cancer cells (AACR 2025) - "In contrast to the Eg5 inhibitor Ispinesib, YF550 does not inhibit normal PBMC proliferation...YF550 has demonstrated synergistic effects when combined with various agents, including Olaparib (PARP inhibitor), PF-07104091 (CDK2 inhibitor), Elimusertib (ATR inhibitor), Volasertib (PLK1 inhibitor), and MMAE, in cellular proliferation assays. In the OVCAR3 ovarian cancer xenograft model, YF550 has shown superior efficacy compared to KIF18A inhibitor AMG650 at a 5 mg/kg dose, with no significant impact on body weight. Furthermore, YF550 induced tumor regression in both the OVCAR8 ovarian and JIMT-1 HER2 positive breast cancer xenograft models. YF550 exhibits superior ADME and PK property suitable for clinical development for CIN+ cancers with high aneuploidy score and has the potential for combination therapy with PD-1/L1 antibodies, PARP1 inhibitors, and MMAE based ADC."

IO biomarker • Late-breaking abstract • Breast Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • HER-2 • KIF18A

Efficacy of ATR kinase inhibitor elimusertib monotherapy or combination in tumors with DNA damage response pathway and other genomic alterations. (PubMed, Mol Cancer Ther) - "The combination of the PI3K inhibitor copanlisib with elimusertib enhanced EFS-2 compared to monotherapy in 3 of 11 models tested. The combination of elimusertib with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib enhanced antitumor activity compared to single agents in PARP-resistant PDX models. Our study shows that ATR inhibition has antitumor activity, including in models with both intrinsic and acquired PARP inhibitor resistance. Further work is needed to better refine patient selection for ATR-based therapies."

Journal • Monotherapy • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • ATM • BRCA1 • BRCA2

Investigating genes and pathways determining sensitivity or resistance to anti-L1cam ADCs in lymphomas (AACR 2025) - "LOF and GOF CRISPR-Cas9 screenings identified genes related to resistance or sensitivity to anti-L1CAM ADCs that could be potentially used as therapeutic targets or biomarkers."

IO biomarker • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma • ABCB1 • ARID1A • CASP9 • CD20 • CDKN2B • CHD4 • FBXW7 • L1CAM • MAPK9 • RAD51B • RIF1 • RIPK1 • SOX11 • TP53

Morphology-guided classification of oral cancer using patient-derived organoids and its therapeutic implications (AACR 2025) - "As a result of evaluating 14 drugs by organoid subtype in a high-throughput drug evaluation system using a 384-well plate, normal-like or grape-like organoids showed a good response to single drug treatment. We observed that dense organoids, which exhibited resistant responses to single drugs, showed an increased synergistic effect when co-treated with the first-line standard chemotherapy drug, cisplatin, and the ATR inhibitor (bay1895344), compared to other subtypes."

Clinical • Tumor mutational burden • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • TMB

Harnessing a radiation-resistant organoid platform to propose novel strategies for precision treatment of advanced oral cancer (AACR 2025) - "The ATR inhibitor, BAY1895344, demonstrated synergistic effects...This study aims to address the limitations of existing preclinical models by utilizing patient-derived organoids that preserve tumor heterogeneity, thereby providing a platform and treatment prediction for clinically relevant research. These findings are anticipated to contribute significantly to the development of precision medicine-based therapeutic strategies for advanced oral cancer."

Metastases • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Unveiling markers of response to ATR inhibitor and TMZ combinations in rare tumor PDXs (AACR 2025) - "The combination of ATR inhibitors with temozolomide (TMZ) [ATRi+TMZ] enhances the cytotoxic effects of TMZ by targeting DNA damage response pathways, particularly in cancer cells with impaired DNA repair mechanisms, offering a promising therapeutic strategy for tumors resistant to conventional treatments. This study utilized gene expression profiling of 38 rare tumor patient-derived xenograft (PDX) models available in the NCI Patient-Derived Models Repository (PDMR) (https://pdmr.cancer.gov) to identify potential biomarkers that predict responses to TMZ combined with either of two ATR inhibitors, i.e., AZD6738 (Ceralasertib) and BAY1895344 (Elimusertib)...Our findings revealed distinct expression signatures associated with favorable responses to two ATR inhibitors when individually combined with TMZ, highlighting candidate markers that could guide treatment decisions. Additional validation in a larger study would establish the potential utility of these candidate genes..."

Biomarker • Oncology • MCM2 • MGMT

Everolimus and Sunitinib potentially work as therapeutic drugs for infantile hemangiomas. (PubMed, Pediatr Res) - "Developed a novel immortalized hemangioma-derived endothelial cell (iHemEC) model that replicates key IH features, overcoming limitations of primary cell models. Identified Sunitinib and Everolimus as promising therapeutic candidates with superior efficacy, supported by transcriptome and protein analyses. Revealed distinct drug mechanisms, with Everolimus targeting PI3K/AKT/mTOR and Sunitinib inducing chromosome instability and DNA damage."

IO biomarker • Journal • Oncology • BCL2 • HIF1A

Elimusertib, a Novel ATR Inhibitor, Induces Anti-Tumor Effects through Replication Catastrophe in Breast Cancers. (PubMed, Cancer Res Treat) - "Moreover, cells under high DNA replication stress were sensitive to elimusertib. Further studies and treatment strategies with elimusertib are warranted for cancers with a high replication rate."

Journal • Ataxia • Breast Cancer • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • Solid Tumor • ANXA5 • CASP7