AZD-7762 / AstraZeneca - LARVOL DELTA

System biological approach identifies heterochromatin modification as an important mechanism of acquired cancer radioresistance (AACR 2025) - "Simultaneously, parallel high-throughput drug screening of our RR and WT cancer cells identified susceptibility to Panobinostat (Pano) - a pan-HDAC inhibitor in vitro and validated in vivo. Combinatorial Pano and AZD7762 - a Chk1 inhibitor exhibited stronger anti-tumor activity against the RR than WT cells (IC50: 0.45 nm [RR] vs 0.60 nm [WT])...Finally, knockdown of class I and II HDACs pointed to reversal of HDAC6 expression as the primary target of Pano. Herein, our systems approach of investigations of our RR cancer models uncovered the importance of the heterochromatin in acquired cancer radioresistance, and presented a potential new molecular vulnerability of RR cancer cells to targeting by epigenetic drugs."

Oncology • Prostate Cancer • CTSD • HDAC6 • JAK1 • RAD51 • RAD51AP1 • SMC1A

Integrated multi-omics analysis and machine learning refine molecular subtypes and clinical outcome for hepatocellular carcinoma. (PubMed, Hereditas) - "Encouragingly, we observed that the high-CMLBS patients may exhibit increased sensitivity to Alpelisib, AZD7762, BMS-536,924, Carmustine, and GDC0810, whereas they may demonstrate reduced sensitivity to Axitinib, AZD6482, AZD8055, Entospletinib, GSK269962A, GSK1904529A, and GSK2606414, suggesting that CMLBS may contribute to the selection of chemotherapeutic agents for HCC patients. Therefore, in-depth examination of data from multi-omics data can provide valuable insights and contribute to the refinement of the molecular classification of HCC. In addition, the CMLBS model demonstrates potential as a screening tool for identifying HCC patients who may derive benefit from immunotherapy, and it possesses practical utility in the clinical management of HCC."

Clinical data • Journal • Hepatocellular Cancer • Oncology • Solid Tumor

Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer. (PubMed, Exp Hematol Oncol) - "We have uncovered HDAC6 as a promising molecular vulnerability that should be explored to treat RR-HNC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor

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

A novel risk model consisting of nine platelet-related gene signatures for predicting prognosis, immune features and drug sensitivity in glioma. (PubMed, Hereditas) - "Nine platelet-related prognostic genes identified as prognostic signatures for glioma were closely associated with the TME and may aid in directing the clinical treatment and prognosis of gliomas."

Biomarker • Gene Signature • Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • KIF20A • SULF2 • TAGLN2

Pan-cancer analysis of oncogenic role of CEP55 and experiment validation in clear cell renal cell carcinoma. (PubMed, Sci Rep) - "We also used Gene Set Cancer Analysis (GSCA) to predict a serious of small molecule CEP55 targeted drugs, such as AZ628, SB52334, SB590885, A-770,041, AZD7762, Elesclomol, panobinostat, BRD-A94377914, and LRRK2-IN-1. Our study indicated that CEP55 overexpression in most caner types was associated with poor prognosis. Notably, CEP55 was closely relevant to immune cell infiltration and impacted the response to immunotherapy and small molecule drugs against cancers."

IO biomarker • Journal • Pan tumor • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CCNA2 • CD4 • CDK1 • CEP55 • KIF11 • LRRK2 • PCNA

Evaluation of BBB permeable Wee1 and Chk1 inhibitors in combination with standard of care for the treatment of glioblastoma (EANO 2024) - "Current therapies such as temozolomide (TMZ) chemotherapy exert suboptimal efficacy, necessitating new therapies such as those targeting nuclear kinases, Wee1 and Chk1...Previous studies combining commercially available Wee1 inhibitor AZD1775 and Chk1 inhibitor AZD7762 showed synergism in melanoma cells... Our novel BBB-permeable Wee1 and Chk1 inhibitors show synergism inducing higher cell kill in patient-derived G7 GBM stem-like cells. Combinations will next be tested with radiation to deduce radiosensitisation effects. With synergism observed between novel BBB-penetrant Wee1 and Chk1 inhibitors, these drugs show potential in becoming viable new therapies for GBM treatment."

Combination therapy • Brain Cancer • CNS Tumor • Glioblastoma • Melanoma • Oncology • Solid Tumor • CDK1 • GNRP • RASGRF1

Development of a Novel CD8+ T Cell-Associated Signature for Prognostic Assessment in Hepatocellular Carcinoma. (PubMed, Cancer Control) - "The CD8+ T-cell-associated signature is expected to be a tool for optimizing individual patient decision-making and monitoring protocols, and to provide new ideas for treatment and prognostic assessment of HCC."

Biomarker • IO biomarker • Journal • Retrospective data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • ANXA2 • CD7 • CD8 • FABP5 • GZMH • IL7R • KLRB1 • RGS2

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons. (PubMed, Cell Mol Life Sci) - "Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic."

Journal • Breast Cancer • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Osteosarcoma • Pain • Sarcoma • Solid Tumor

m6A- and m5C- modified lncRNAs orchestrate the prognosis in cutaneous melanoma and m6A- modified LINC00893 regulates cutaneous melanoma cell metastasis. (PubMed, Skin Res Technol) - "We made an analysis of m6A- and m5C- related lncRNAs in melanoma samples and a prediction of these lncRNAs' role in prognosis, tumor microenvironment, immune infiltration, and clinicopathological features. We also found that LINC00893, which is potentially regulated by m6A modification, could serve as a tumor-suppressor in melanoma and play an inhibitory role in melanoma metastasis."

Biomarker • Journal • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • AGAP2-AS1 • METTL3 • MIAT • SEMA6A • YTHDF3

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons. (PubMed, Res Sq) - "Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic."

Journal • Breast Cancer • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Osteosarcoma • Pain • Sarcoma • Solid Tumor

Developing targeted therapies for neuroblastoma by dissecting the effects of metabolic reprogramming on tumor microenvironments and progression. (PubMed, Theranostics) - "AZD7762 and etoposide were identified as potent therapeutics against MPS-I and II NB, respectively. This study provides deep insights into the molecular mechanisms underlying metabolic reprogramming-mediated malignant progression of NB. It also sheds light on developing targeted medications guided by the novel precise risk prognostication approaches, which could contribute to a significantly improved therapeutic strategy for NB."

Biomarker • Journal • Tumor microenvironment • CNS Disorders • CNS Tumor • Neuroblastoma • Oncology • Psychiatry • Solid Tumor • MYCN

DIFFERENTIAL RESPONSE TO ATR/CHK1 INHIBITION IN PRELEUKEMIA AND TRANSFORMED LEUKEMIA IN AN MLL-ENL MODEL OF LEUKEMOGENESIS (EHA 2024) - " We tested the in vivo effects of the pharmacologically characterized ATR inhibitors (ATRi) AZD-6738(ceralasertib), BAY-1895344 (elimusertib) and Chk1i AZD-7762 using previously described MLL​ENL mice. First, we analyzed the in vivo consequences of ATR inhibition during preleukemia progressing to leukemia, i. e. ,early in leukemogenesis. Preleukemia cells with active MLL-ENL revealed enrichment of gene sets related toE2F targets, cell cycle checkpoints, and DNA repair. Provision of the milder ATRi ceralasertib resulted in anincrease of immature c-kit+/Mac-1+ cells in BM and spleen."

Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • CHEK1 • CHEK2 • FLT3

A risk scoring model based on M2 macrophage-related genes for predicting prognosis of HBV-related hepatocellular carcinoma (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "The MRG-based risk scoring model can accurately predict the prognosis of HBV-related HCC and reveal the differences in tumor microenvironment to guide precision treatment of the patients."

Journal • Gastrointestinal Cancer • Hepatitis B • Hepatocellular Cancer • Hepatology • Infectious Disease • Oncology • Solid Tumor • TRIM27

Construction of a Novel MitochondriaAssociated Gene Model for Assessing ESCC Immune Microenvironment and Predicting Survival. (PubMed, J Microbiol Biotechnol) - "AZD1332 and AZD7762 were more effective for patients in the low-risk group, whereas Entinostat, Nilotinib, Ruxolutinib, and Wnt.c59 were more effective for patients in the high-risk group. Knockdown of TYMS significantly inhibited the proliferation and invasive ability of ESCC cells in vitro. Overall, our MAR model provides stable and reliable results and may be used as a prognostic biomarker for personalized treatment of patients with ESCC."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • TYMS

Actin filament-associated protein 1-antisense RNA1 promotes the development and invasion of tongue squamous cell carcinoma via the AFAP1-AS1/miR-133a-5p/ZIC2 axis. (PubMed, J Gene Med) - "The upregulation of lncRNA AFAP1-AS1, which increases TSCC cell viability, migration, proliferation and invasion via the AFAP1-AS1/miR-133a-5p/ZIC2 axis, aids in the progression of TSCC."

Journal • Infectious Disease • Oncology • Squamous Cell Carcinoma • Tongue Carcinoma • AFAP1-AS1 • ZIC2

Checkpoint kinase 2 controls insulin secretion and glucose homeostasis. (PubMed, Nat Chem Biol) - "Here we performed a chemical screen and identified AZD7762, a compound that potentiates glucose-stimulated insulin secretion (GSIS) of a human β cell line, healthy and type 2 diabetic (T2D) human islets and primary cynomolgus macaque islets...Finally, untargeted metabolic profiling demonstrated the key role of the CHEK2-PP2A-PLK1-G6PD-PPP pathway in insulin secretion. This study successfully identifies a previously unknown insulin secretion regulating pathway that is conserved across rodents, cynomolgus macaques and human β cells in both healthy and T2D conditions."

Journal • Diabetes • Type 2 Diabetes Mellitus • CHEK2 • PLK1

The essential role of DNA repair in the pharmacological activities of AST-3424 (ESMO 2023) - "However, enhancement of AST-3424 cytotoxicity by G2 arrest inhibitors, including adavosertib, AZD7762 and ceralasertib was only observed in HT29 but not in H460 cells. Conclusions DNA repair plays an essential role in AST-3424-mediated in vitro biological activities and in vivo anti-tumor activity. The preclinical data presented in this study support a new approach for cancer treatment."

Oncology • Pancreatic Cancer • AKR1C3 • BRCA • CDK1 • RAD51

SIRT3-dependent mitochondrial redox homeostasis mitigates CHK1 inhibition combined with gemcitabine treatment induced cardiotoxicity in hiPSC-CMs and mice. (PubMed, Arch Toxicol) - "Mice were intraperitoneally injected with 25 mg/kg CHK1 inhibitor AZD7762 and 20 mg/kg gemcitabine for 3 weeks. Further hiPSC-CMs and mice experiments demonstrated that SIRT3 overexpression maintained mitochondrial function while alleviating CM pyroptosis, and thereby improving mice cardiac function. In summary, our results suggest that targeting SIRT3 could represent a novel therapeutic approach for clinical prevention and treatment of cardiotoxicity induced by CHK1 inhibition and gemcitabine."

Journal • Preclinical • Cardiovascular • Oncology • SIRT3

AZD7762 induces CRBN dependent BAG3 degradation through ubiquitin-proteasome pathway. (PubMed, Anticancer Drugs) - "CRBN, an E3 ligase, was identified to bind to BAG3 and mediated BAG3 ubiquitination in the presence of AZD7762. By targeting Chk1 and BAG3, two ideal therapeutic targets in cancer treatment, AZD7762 would be a powerful chemotherapy agent in the future."

Journal • Oncology • Targeted Protein Degradation • ANXA5 • CRBN

Systematic high-throughput combination drug screen to enhance poly (ADP-ribose) polymerase (PARP) inhibitor efficacy in ovarian cancer. (ASCO 2023) - "Following a combination screen with olaparib, the compounds selected for final validation were: AZD 7762 (CHK1/2 inhibitor), dinaciclib (pan-CDK inhibitor), onalespib (HSP90 inhibitor), and SN-38 (topoisomerase 1 inhibitor)...In MTT assays, we identified robust synergy between olaparib and CT7439, a next-generation oral CDK12/13 inhibitor, with a mean Bliss synergy score of 1.31 and scores as high as 22.03 at certain concentrations in the non-HRD model OVCAR-5... Pairing a PARP inhibitor and CDK inhibitor, a strategy identified by a high-throughput drug screen and known to impair homologous recombination, resulted in robust synergy in both HRD and non-HRD ovarian cancer models. Clinical translation of this combination may enhance the efficacy of PARP inhibitors in patients with ovarian cancer. >"

Clinical • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • CDK12 • HRD

Prognostic implication of heterogeneity and trajectory progression induced by enzalutamide in prostate cancer. (PubMed, Front Endocrinol (Lausanne)) - "High-ENZ-sig patients were more sensitive to cell cycle-targeted drugs (MK-1775, AZD7762, and MK-8776) than low-ENZ-sig patients in PCa. Our results provided evidence and insight on the potential utility of ENZ-sig in PCa prognosis and combination therapy strategy of enzalutamide and cell cycle-targeted compounds in treating PCa."

Heterogeneity • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ACPP • COL5A2 • SH3BGRL • TUBA1A

Pan-Cancer analysis and experimental validation identify the oncogenic nature of ESPL1: Potential therapeutic target in colorectal cancer. (PubMed, Front Immunol) - "Additionally, the higher the expression of ESPL1 in organoids, the greater the sensitivity to PHA-793887, PAC-1, and AZD7762. Taken together, our study provides evidence that ESPL1 may implicate tumorigenesis and disease progression across multiple cancer types, highlighting its potential utility as both a prognostic indicator and therapeutic target."

Journal • Pan tumor • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Constructing a novel mitochondrial-related gene signature for evaluating the tumor immune microenvironment and predicting survival in stomach adenocarcinoma. (PubMed, J Transl Med) - "Our results suggest that the mitochondrial-related risk model could be a reliable prognostic biomarker for personalized treatment of STAD patients."

Gene Signature • IO biomarker • Journal • Tumor mutational burden • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Immune Modulation • Metabolic Disorders • Oncology • Solid Tumor • FKBP10 • NOX4 • TMB

RILPL2 is associated with the progression and prognosis of cervical squamous cell carcinoma and endocervical adenocarcinoma. (PubMed, Am J Transl Res) - "Patients with high RILPL2 expression showed lower resistance to small molecule drugs used in CESC progressions, such as Methotrexate, AZD7762, and Vinblastine, and a higher response rate to immunotherapy. Low RILPL2 expression was closely associated with the onset, progression, and poor prognosis of CESC. RILPL2 might be a promising optional biomarker for CESC patients' diagnosis and prognosis."

IO biomarker • Journal • Breast Cancer • Cervical Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma