AT7519 / Novartis, Otsuka - LARVOL DELTA

Beyond 2D Cultures: Establishment of Lung Cancer Organoids and Ex Vivo Explant for Enhanced Preclinical Therapeutic Screening (IASLC-WCLC 2026) - "Results : A PDLE was established with an EGFR ex19del, MET FISH amplified tumor and treated with osimertinib and crizotinib in combination...Functional drug screen with 58 compounds treated at clinically relevant doses identified sensitivity to chemotherapy drugs (doxorubicin, Gemcitabine and Paclitaxel) and also to CDK (AT7519) and Chk (CHIR-124) inhibitors, suggesting the tumor might have abnormal checkpoints controls...PDLEs serve as a rapid system to interrogate early immune TME remodeling and investigate synergistic drug effects, while PDLOs provide a scalable model for drug screen and resistance profiling. Collectively, these models provide a mechanistic rationale for clinical treatment strategies and a pathway toward personalized oncology beyond traditional 2D cultures."

IO biomarker • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • EGFR • MET • MUC5AC • Napsin A • NKX2-1 • TP53

Pan-CDK and PLK1 inhibitors as a novel approach for targeted treatment of adrenocortical carcinomas. (PubMed, Eur J Endocrinol) - "This study investigated the anti-tumour efficacy of the pan-CDK inhibitors (CDKi) dinaciclib, AT7519, and SNS-032; the CDK1-cyclin B1 inhibitor cucurbitacin E (curE); the PLK1 inhibitors (PLK1i) poloxin and plogosertib; and selected combination strategies in four genetically heterogeneous ACC cell lines (NCI-H295R, JIL-2266, MUC-1, TVBF-7) and primary cultures. These results identify dinaciclib and plogosertib as the most effective inhibitors across all ACC models tested. Their simultaneous action on multiple checkpoints, alongside with their synergistic effect in selected cell lines, suggest a potential benefit of their use in ACC that needs to be further investigated in vivo."

Journal • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CCNB1 • CCNE1 • CDK1 • CDKN1A • CYP17A1 • CYP1A2 • CYP21A2 • MUC1

NOTCH2NLA gene amplification is associated with poor prognosis in breast cancer. (PubMed, Discov Oncol) - "In vitro experiments demonstrated that overexpression of NOTCH2NLA in breast cancer cells promoted cell growth and enhanced sensitivity to AT-7519 treatment. Collectively, our findings suggest that NOTCH2NLA amplification may be a new prognostic marker of BRCA and cell cycle inhibitors were more suitable for therapy on BRCA patients with NOTCH2NLA amplification."

Journal • Breast Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • BRCA

Artificial exosomes synergistically reshape sepsis immune homeostasis by modulating neutrophil fate and blocking PD-1/PD-L1. (PubMed, Cell Rep Med) - "It comprises a pH-responsive bovine serum albumin core carrying AT7519, a cyclin-dependent kinase inhibitor, cloaked with macrophage membrane presenting PD-1...By engaging PD-L1, AT@NV-PD1 also alleviates T cell exhaustion, reduces immunosuppression, and promotes immune homeostasis. In conclusion, AT@NV-PD1 represents a sepsis therapy by precisely regulating neutrophil fate and rebuilding immune balance."

Journal • Infectious Disease • Inflammation • Septic Shock • PD-L1

Suppressing liver metastasis growth by inducing the endogenous expression of the tumor suppressor miR-34a by small synthetic molecules (AACR 2025) - "However, when validating these compounds, only 6 (AT7519, A-674563, BBI503, PCM0240249, KRIBB and SB273005) out of 9 compounds that were tested -induced miR-34a promoter activation and only 2 (AT7519 and A-674563) out of the 6, also caused miR-34a secretion from HepG2, a human hepatoblastoma cell line. Induction of miR-34a using small synthetic molecules is a novel therapeutic approach to eradicate CRC liver metastasis."

Late-breaking abstract • Breast Cancer • Colorectal Cancer • Hepatoblastoma • Melanoma • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • MIR34A

Comprehensive analysis of palmitoylation-related proteins for prognostic risk evaluation and tumor immune microenvironment assessment in glioma. (PubMed, Front Immunol) - "The PRRS emerges as a dependable prognostic biomarker, offering therapeutic advantages in the context of chemotherapy and immunotherapy, and potentially aiding in clinical decision-making for glioma patients. The identified compounds, AT-7519, BIX02189, and THZ-2-101-1, may potentially exert inhibitory effects on the malignant progression of glioma by targeting palmitoylation-related proteins."

Biomarker • IO biomarker • Journal • Brain Cancer • Glioma • Oncology • Solid Tumor

Development of a multi-indicator risk prediction model for cervical cancer associated with benzo[a]pyrene and nicotine exposure: A multi-omics study integrating toxicological analyses and molecular docking. (PubMed, Ecotoxicol Environ Saf) - "Risk prediction models based on multi-omics data and machine learning algorithms provide potential reference targets for prognosis prediction and personalised treatment of cervical cancer patients. The results of this study provide important insights into the understanding of the health risks of cervical cancer associated with Benzo[a]pyrene and Nicotine exposures and the development of preventive and therapeutic strategies for cervical cancer, which may contribute to the development of precision medicine for cervical cancer."

Journal • Cervical Cancer • Oncology • Solid Tumor • SLAMF6

Novel SARS-CoV-2 allosteric inhibitors that destabilize the Main Protease Mpro dimer. (PubMed, Int J Biol Macromol) - "Molecular modelling studies suggested that compounds 1 and 11 bind Mpro similarly to the allosteric inhibitor AT7519. Small-angle X-ray scattering studies revealed that 1 and 11 strongly shift Mpro equilibrium to the monomeric form, while the allosteric inhibitor pelitinib and the catalytic inhibitors nirmatrelvir and GC376 stabilize the dimer. Compounds 1 and 11 inhibited Mpro proteolytic activity in SARS-CoV-2 infected cells acting as allosteric inhibitors that stabilize the monomeric form. In conclusion, we validated an allosteric site in Mpro that could be exploited for the development of effective anti-SARS-CoV-2 antivirals targeting Mpro with a novel mechanism."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Identification of a Potent and Selective CDK9 Degrader as a Targeted Therapeutic Option for the Treatment of Small-Cell Lung Cancer. (PubMed, J Med Chem) - "In this study, a potent and selective CDK9 degrader, C3, was developed through PROTAC modification of the CDK9 inhibitor, AT-7519...Our findings indicate that the targeted degradation of CDK9 could become a viable strategy for treating SCLC, highlighting its potential therapeutic value. Additionally, this research offers a general structural optimization and evaluation strategy to improve the degradative selectivity, metabolic stability, and oral availability of PROTAC molecules."

Journal • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Targeted Protein Degradation • CDK9

Identification of C/EBPδ-Modifying Compounds as Potential Anticancer Agents Using a High-Throughput Drug Screen. (PubMed, J Cell Mol Med) - "We confirmed the potential importance of cell cycle-mediated regulation of C/EBPδ by showing that four of the most potent C/EBPδ activators-R547, PHA793387, AZD5438 and AT7519, all multi-cyclin-dependent kinase (CDK) inhibitors-limited the clonal expansion of PDAC cells. Next to providing a valuable selection of C/EBPδ-modulating compounds for the use in preclinical studies, this report contributes to our understanding of the molecular regulatory mechanisms of C/EBPδ in general and in PDAC in particular."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CEBPD

The cyclin-dependent kinase inhibitor AT7519 is a human RORγt agonist. (PubMed, Immunol Cell Biol) - "After exposure to AT7519 during differentiation, primary human CD4+ T cells presented increased expression of IL17A/F, IFNG and GZMB and decreased expression of PDCD1 and CTLA4. These findings elucidate a previously unrecognized facet of AT7519 activity and suggest the potential incorporation of this molecule into immune therapies to augment the effectiveness of diverse anticancer strategies involving anti-programmed cell death protein 1 (anti-PD-1) and anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) regimens."

IO biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • CD4 • GZMB • IFNG • IL17A

Discovery of pyrazole-based analogs as CDK2 inhibitors with apoptotic-inducing activity: design, synthesis and molecular dynamics study. (PubMed, RSC Adv) - "In silico molecular docking studies revealed that compounds 4, 7a, 7d, and 9 adopt a similar binding mode as AT7519 (I) within the CDK2 binding site...Based on these findings, it was concluded that the synthesized pyrazole derivatives, particularly compound 4, show potent CDK2 inhibition and significant anticancer activity, with promising drug-like properties and minimal toxicity. This positions them as strong candidates for further development as CDK2-targeting anticancer agents."

Journal • Breast Cancer • Oncology • Solid Tumor • CCNA2

Prognostic implication and immunotherapy response prediction of a novel ubiquitination-related gene signature in liver cancer. (PubMed, Aging (Albany NY)) - "In the high-risk group, erlotinib showed higher IC50 values compared to the low-risk group which exhibited higher IC50 values for VX-11e, AKT inhibitor VIII, AT-7519, BMS345541, Bortezomib, CP466722, FMK, and JNK-9L. The results of RT-qPCR revealed that the expression of four UEGs was higher in tumor tissue as compared to normal tissue. Based on the genes that were expressed differently and associated with ubiquitination-related tumor categorization, we have developed a pattern of four genes and a strong nomogram that can predict the prognosis of HCC, which could be useful in identifying and managing HCC."

Gene Signature • IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • MCM10 • TRIM54

Novel ferroptosis signature for improving prediction of prognosis and indicating gene targets from single-cell level in oral squamous cell carcinoma. (PubMed, Heliyon) - "Finally, we found that CA9 and CAV1 could regulate OSCC proliferation, migration and ferroptosis in vitro. A novel 10-FRDEGs risk scoring model can predict the prognosis of patients with OSCC.Further,5Z)-7-Oxozeaenol, AT-7519, KIN001-266 are potential chemotherapeutic agents for OSCC.Moreover, we identified CA9、CAV1 as potential molecular target for the treatment of OSCC.Our findings provide new directions for prognostic assessment and precise treatment of oral cell squamous carcinoma."

Journal • Oncology • Oral Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CA9 • CAV1

An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase. (PubMed, Int J Biol Macromol) - "In this study, we explored the binding characteristics and inhibiting process of Mpro activity by two recently reported allosteric inhibitors, pelitinib and AT7519 which were obtained by the X-ray screening experiments, to probe the allosteric mechanism via molecular dynamic (MD) simulations...In summary, our findings provide the detailed working mechanism for the two experimentally observed allosteric sites of Mpro. These allosteric sites greatly enhance the 'druggability' of Mpro and represent attractive targets for the development of new Mpro inhibitors."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Onalespib and CDKI AT7519 in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery (clinicaltrials.gov) - P1 | N=29 | Active, not recruiting | Sponsor: National Cancer Institute (NCI)

Metastases • Surgery • Trial completion date • Oncology • Solid Tumor

Degradation by Design: New Cyclin K Degraders from Old CDK Inhibitors. (PubMed, ACS Chem Biol) - "We used these findings to convert the pan-CDK inhibitors dinaciclib and AT-7519 to Cyclin K degraders, leading to a novel dinaciclib-based compound with improved degradation activity compared to CR8 and confirm the mechanism of degradation. These results suggest that general design principles can be generated for the development and optimization of monovalent degraders."

Journal • Targeted Protein Degradation

A precise prognostic signature in CTNNB1-mutant hepatocellular carcinoma: Prognosis prediction and precision treatment exploration. (PubMed, Heliyon) - "Subsequently, we suggested that AT-7519 and PHA-793887 might be potential drug agents for high-risk patients. Besides, we explored the potential drug targets and agents for patients with high risk. Our findings offered a fresh idea for personalized prognosis management in HCCs with CTNNB1 mutations and threw new insight for precise treatment in HCCs as well."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CTNNB1

Comprehensive Profiling and Therapeutic Insights into Differentially Expressed Genes in Hepatocellular Carcinoma. (PubMed, Cancers (Basel)) - "Potential therapeutic chemicals are alvocidib, AT-7519, kenpaullone, PHA-793887, JNJ-7706621, danusertibe, doxorubicin and analogues, mitoxantrone, podofilox, teniposide, and amonafide. This multi-omic study offers a comprehensive view of DEGs in HCC, shedding light on potential therapeutic targets and drug repurposing opportunities."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • AURKA • CCNB1 • CDK1 • RRM2 • TOP2A

Examination of the Impact of Triazole Position within Linkers on Solubility and Lipophilicity of a CDK9 Degrader Series. (PubMed, ACS Med Chem Lett) - "In this work, a series of AT7519-based CDK9 degraders was assembled using click chemistry, facilitating the tuning of aqueous solubility and lipophilicity while retaining their linker type and molecular weight. Using chromatographic logD and kinetic solubility experiments, we show that degraders with similar chemical constitution but varied position of the embedded triazole demonstrate different lipophilicity and aqueous solubility properties. Overall, this work highlights the impact of triazole placement on linker composition through application of click chemistry for degrader synthesis and its ability to be used to promote the achievement of favorable physicochemical properties."

Journal • Targeted Protein Degradation • CDK9

Anti-hepatocellular carcinoma activity of the cyclin-dependent kinase inhibitor AT7519. (PubMed, Biomed Pharmacother) - "Moreover, we showed that the concomitant use of AT7519 with gefitinib or cabozantinib sensitized HCC cells to these drugs. Thus, our research indicates that AT7519 is worth considering in monotherapy for hepatocellular carcinoma patients or in combination with other drugs, e.g., gefitinib or cabozantinib."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Analysis of AT7519 as a pro-resolution compound in an acetaminophen-induced mouse model of acute inflammation by UPLC-MS/MS. (PubMed, J Inflamm (Lond)) - "We optimised an LC-MS/MS method to quantify both AT7519 and APAP in mouse serum (50 µL), using labelled internal standards. Application of this method to a mouse model of APAP toxicity proved effective in accurately measuring APAP and AT7519 concentrations after i.p. dosing. AT7519 was significantly higher in mice with APAP toxicity, indicating hepatic metabolism of this CDKI, but there was no correlation with markers of hepatic damage or proliferation, demonstrating that this dose of AT7519 (10 mg/kg) does not contribute to hepatic damage or repair. This optimised method can be used for future investigations of AT7519 in APAP in mice."

Journal • Preclinical • Hepatology • Inflammation • Liver Failure

AZD5438 a GSK-3a/b and CDK inhibitor is antiapoptotic modulates mitochondrial activity and protects human neurons from mitochondrial toxins. (PubMed, Sci Rep) - "To investigate the actions of this class of drug further, we compared the ability of kenpaullone, alsterpaullone, 1-azakenapaullone, AZD5438, AT7519 (CDK and GSK-3a/b inhibitors) and dexpramipexole and olesoxime (mitochondrial permeability transition pore inhibitors) to prevent CCCP mediated mitochondrial depolarisation and found that AZD5438 and AT7519, were the most effective. Importantly, experiments in human iPSC derived cortical and midbrain neurons showed AZD5438 mediated significant protective effects, preventing the neuronal cell death, and collapse in the neurite and mitochondrial network associated with rotenone treatment. These results suggest drugs that target GSK-3a/b and CDKs should be developed and assessed further as they may have significant therapeutic potential."

Journal • PPARGC1A

Bifunctional degraders of cyclin dependent kinase 9 (CDK9): Probing the relationship between linker length, properties, and selective protein degradation. (PubMed, Eur J Med Chem) - "In this study, a series of protein degraders was developed, employing the clinically tested CDK inhibitor AT7519. The purpose of this study was to examine the effect that linker composition, specifically chain length, would have on potency. In addition to establishing a baseline of activity for various linker compositions, two distinct homologous series, a fully alkyl series and an amide-containing series, were prepared, demonstrating the dependence of degrader potency in these series on linker length and the correlation with predicted physicochemical properties."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CDK9

Discovery of a Potent and Selective CDKL5/GSK3 Chemical Probe That Is Neuroprotective. (PubMed, ACS Chem Neurosci) - "We prepared analogs of AT-7519, a compound that has advanced to phase II clinical trials and is a known inhibitor of several cyclin-dependent kinases (CDKs) and cyclin-dependent kinase-like kinases (CDKLs)...Finally, we used our chemical probe pair (2 and 4) to demonstrate that inhibition of CDKL5 and/or GSK3α/β promotes the survival of human motor neurons exposed to endoplasmic reticulum stress. We have demonstrated a neuroprotective phenotype elicited by our chemical probe pair and exemplified the utility of our compounds to characterize the role of CDKL5/GSK3 in neurons and beyond."

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