AT7519 / Novartis, Otsuka - LARVOL DELTA

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 • Gastric Cancer • Hepatoblastoma • Melanoma • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • MIR34A

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."

Journal

An Overview of CDK Enzyme Inhibitors in Cancer Therapy. (PubMed, Curr Cancer Drug Targets) - "We have mentioned first-generation pan-CDKIs, flavopiridol and roscovitine, as well as second-generation CDKIs, dinaciclib, P276-00, AT7519, TG02, roniciclib, and RGB-286638, based on their research phases, clinical trials, and cancer targeting. CDKIs are CDK4/6, CDK7, CDK9, and CDK12 inhibitors. Finally, we have looked into the efficacy of CDK inhibitors and PD1/PDL1 antibodies when used together, which could lead to the development of a viable cancer treatment strategy."

Journal • Oncology • CDK4 • CDK7 • CDK9

Involvement of aberrant acinar cell proliferation in scopolamine-induced dry eye mice. (PubMed, Exp Eye Res) - "More importantly, both prophylactic and therapeutic administration of the cyclin-dependent kinase (CDK) inhibitor AT7519 rescued the tear reduction and alleviated dry eye severity in the scopolamine-treated mice, including corneal epithelial barrier function, lacrimal and corneal inflammation, and conjunctival goblet cell density. Therefore, we conclude that aberrant acinar cell proliferation is involved in the scopolamine-induced tear reduction and dry eye onset, which can be improved by AT7519 treatment."

Journal • Preclinical • Dry Eye Disease • Immunology • Inflammation • Keratitis • Ocular Inflammation • Ophthalmology • PCNA

The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest. (PubMed, Cell Death Dis) - "In the glioblastoma intracranial and subcutaneous xenograft assays, tumor volume was significantly reduced after treatment with AT7519. In summary, AT7519 induces cell death through multiple pathways and inhibits glioblastoma growth, indicating that AT7519 is a potential chemical available for GBM treatment."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Immunology • Oncology • Solid Tumor • CASP3 • CDK1 • GSDME

Phase 1 study of onalespib, HSP90 inhibitor, and AT7519M, CDK9 inhibitor, in patients with advanced solid tumors. (ASCO 2017) - P1; "At this time, DL1 has completed enrollment; accrual is ongoing with measurement of HSP90 client proteins and HSP70 levels in patient plasma and PBMC samples. This trial is open through the ETCTN."

P1 data • Biosimilar • Oncology • Ophthalmology

Comprehensive analysis of the glutathione S-transferase Mu (GSTM) gene family in ovarian cancer identifies prognostic and expression significance. (PubMed, Front Oncol) - "RT-qPCR analysis confirmed the effect of AICAR, AT-7519, PHA-793887 and PI-103 on the mRNA levels of GSTM3/4. GSTM3 was negatively correlated with OC prognosis, and associated with OC chemoresistance and immune escape. This gene may serve as potential prognostic biomarkers and therapeutic target for OC patients."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • GSTM1 • GSTM5 • GSTP1

Predicting Chemo-Radiotherapy Sensitivity With Concordant Survival Benefit in Non-Small Cell Lung Cancer via Computed Tomography Derived Radiomic Features. (PubMed, Front Oncol) - "The therapeutic efficacy of AT-7519 was validated that significantly more resistant genes were down-regulated induced by AT-7519, and the degree gradually increased with the enhanced doses. This study illustrated that radiomic signature could non-invasively predict therapeutic efficacy of patients with NSCLC receiving CCR, and indicated that patients with CCR resistance might benefit from AT-7519 or CCR treatment combined with AT-7519."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Delayed neutrophil apoptosis may enhance NET formation in ARDS. (PubMed, Respir Res) - "Neutrophils with extended lifespan in ARDS usually enhance NET formation, which aggravates inflammation. Enhancing neutrophil apoptosis in ARDS can reduce the formation of NETs, inhibit inflammation, and consequently alleviate ARDS."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CSF2