AT7519

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.

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.

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.

P1, N=29, Active, not recruiting, National Cancer Institute (NCI)

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.

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.

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.

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.

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.

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.

Further evaluation of this role has been hampered by the lack of selective pharmacological inhibitors. Herein, we provide a comprehensive overview about the therapeutic potential of targeting CDK3 in cancer.

Taken together, AT519 exhibits great anti-tumor effects in lung cancer, and the mechanism was related closely to IL-6/STAT3 signaling pathway, which suggests the important roles of STAT3 in CDKs inhibitors. AT7519 might be a novel potential therapeutic agent based on this rationale.

According to the obtained results, some of these drugs including vorinostat, mocetinostat, alvocidib, CGP-60474, BMS-387032, AT-7519, and curcumin have significant functional similarity and structural correlation with FDA-approved breast cancer drugs. Moreover, the experimental approach verified curcumin as an effective therapeutic agent for HER2 positive breast cancer. Hence, our work suggested that some repurposed drugs based on gene expression data can be noticed as potential drugs for the treatment of HER2-positive breast cancer.

We further found that compared to patients with low-risk score, patients with high-risk score had higher sensitivity to some drugs of targeting the immune microenvironment, including TGFβ receptor inhibitors SB525334 ( P <0.0001) and SB505124 ( P <0.0001) and immunomodulator Lenalidomide ( P =0.041), as well as NF-κB inhibitors Parthenolide ( P <0.0001) and TPCA-1 ( P <0.0001) and JAK inhibitors Ruxolitinib ( P =0.014) and TG101348 ( P =0.0053), accompanying with significantly lower IC50 values. In addition, another common chemotherapeutic drug Gemcitabine was also predicted to be more sensitive for patients with high-risk score ( P =0.047). Other targeted drugs such as Aurora kinase inhibitors VX-680 ( P <0.0001) and ZM-447439 ( P =0.014), Bcl-2 inhibitors Obatoclax Mesylate ( P =0.00036) and Navitoclax ( P <0.0001), and CDK inhibitors Roscovitine ( P =0.0012), AT-7519 ( P =0.0033), PHA-793887 ( P <0.0001) and THZ2-49 ( P =0.0053) also exhibited higher drug sensitivity for patients with high-risk score. Conclusions : PIM1 mutations play a vital role in patient risk stratification and provide novel insights into therapeutic decision making for DLBCL patients with high-risk score.

Among 1278 significantly correlated gene-drug pairs, copy number of GNA13 and DNA damage response genes CBL, DNMT3A, and PPM1D were most significantly correlated with cytotoxicity; the drugs most commonly associated with these genes were PI3K/mTOR inhibitor PIK-75, and CDK inhibitors P276-00, SNS-032, AT7519, flavopiridol and dinaciclib. Together, our data defined individualized dose-dependent relationships between copy number gains of PI3K and STAT family genes particularly on 17q and susceptibility to PI3K and cell cycle agents in neuroblastoma. Integration of genomic profiling and drug screening of patient-derived models of neuroblastoma can quantitatively define copy number-dependent sensitivities to targeted inhibitors, which can guide personalized therapy for such mutationally quiet cancers.

Using human ovarian cancer xenograft mouse model, we confirm the in vivo efficacy of AT7519 alone, and the synergistic effects of AT7519 and cisplatin in combination, at doses that cause minimal toxicity in mice. Our findings provide systematic pre-clinical evidence to support the initialization of clinical trials of the AT7519 and cisplatin combination for the treatment of ovarian cancer.

We reviewed first-generation pan-CDKIs Flavopiridol and Roscovitine, and second-generation CDKIs Dinaciclib, P276-00, AT7519, TG02, Roniciclib, RGB-286638 by focusing on their developing stages, clinical trials and targeting cancers. These CDKIs include CDK4/6, CDK7, CDK9, and CDK12/13 inhibitors. Finally, the efficacy and discrepancy of combination therapy with CDK inhibitors and PD1/PDL1 antibodies were analyzed, which might give insights into the development of promising strategy for cancer treatment.

In fact, the Phase I clinical trials of the latest, highly specific CDK9 inhibitor BAY1251152, against different solid tumors have shown good anti-tumor and on-target activities and pharmacokinetics, combined with manageable safety profile while the phase I and II clinical trials of another inhibitor AT-7519 have been undertaken or are undergoing. To enhance the effectiveness and target diversity and reduce potential drug-resistance, the future of CDK9 inhibition would likely involve combining CDK9 inhibitors with inhibitors like those against BRD4, SEC, MYC, MCL-1 and HSP90.

A link between CDK hyperactivation and mt KRas dependency was uncovered and pharmacologically-exploited to abrogate mt KRas-driven pancreatic cancer in highly relevant models, warranting clinical investigations of AT7519 in pancreatic cancer patients.

The blockage of cell cycle, as announced by induction of sub-G1 arrest as well as reduced S phase, resulted in a significant decrease in survival of acute promyelocytic leukemia (APL)-derived NB4 cells, as the most sensitive cell line, either as monotherapy or in combination with arsenic trioxide. Anti-leukemic effects of the inhibitor were further verified by apoptosis analysis, where we discovered that AT7519 induced apoptosis via alteration of pro- and anti-apoptotic genes in NB4. All in all, this study proposed that AT7519 is a rewarding agent opposed to APL; however, additional examinations should be performed to determine the advantages of this inhibitor in clinical setting.

The two-mRNA signature (CNFN and DEPDC1) could serve as an independent biomarker to predict LOI risk and provide new insights into the mechanisms underlying LOI in HNSCC. In addition, the small molecular agents appear promising for LOI treatment.

Our work is the first to report anti-NPC activities of AT7519. Our preclinical evidence suggests that AT7519 is a useful addition to overcome NPC chemo-resistance.

Small-molecule drugs targeting the CDK9 kinase, dinaciclib, flavopiridol, roscovitine, AT-7519, SNS-032, and DRB, diminished MDM4 levels and activated p53 in A375 melanoma and MCF7 breast carcinoma cells with only a limited effect on MDM2...CDK9 inhibitor atuveciclib downregulated MDM4 and enhanced p53 activity induced by nutlin-3a, an inhibitor of p53-MDM2 interaction, and synergized with nutlin-3a in killing A375 melanoma cells. Furthermore, we found that human pluripotent stem cell lines express significant levels of MDM4, which are also maintained by CDK9 activity. In summary, we show that CDK9 activity is essential for the maintenance of high levels of MDM4 in human cells, and drugs targeting CDK9 might restore p53 tumor suppressor function in malignancies overexpressing MDM4.