seliciclib (CYC202)

Remarkably, they demonstrated potent EGFR inhibition, with IC50 values of 0.026, 0.067, and 0.04 μM and inhibition percentages of 92.6%, 89.8%, and 91.2%, respectively, when compared to Erlotinib (IC50 = 0.03 μM, 95.4%). Furthermore, these compounds exhibited potent CDK-2 inhibition, with IC50 values of 0.301, 0.345, and 0.557 μM and inhibition percentages of 91.9%, 89.4%, and 88.7%, respectively, in contrast to Roscovitine (IC50 = 0.556 μM, 92.1%)...Treatment with 5g increased the gene expression of pro-apoptotic genes P53, Bax, caspases 3, 8, and 9 with notable fold changes while decreasing the expression of the anti-apoptotic gene Bcl-2. Molecular docking and dynamic simulations (100 ns simulation using AMBER22) were conducted to investigate the binding mode of the most potent candidates, namely, 5g, 5l, and 5n, within the active sites of EGFR and CDK-2.

Compound 7e exhibited the most potent cytotoxic activity against A549 cell line (IC50: 0.155 µM) while compound 8d showed the most potent one against MCF7 cell line (IC50: 0.170 µM) in comparison with doxorubicin...Our findings by docking and experimental studies that compound 7e is a potent CDK2 inhibitor with IC50 of 0.149 µM, compared to the Roscovitine control drug with IC50 of 0.380 µM. We also found that compound 8d is a significant DHFR inhibitor with an IC50 of 0.199 µM, compared to Methotrexate control drug with IC50 of 0.131 µM. Evaluation of the antioxidant properties of ten compounds was also studied in comparison with Vitamin C. Compounds 1, 3, 6, 7c and 8e have higher antioxidant activity than Vitamin C which mean that these compounds can used as potent antioxidant drugs.

CDK5 might play important roles in bladder cancer progression and be a potential diagnostic and therapeutic target in the near future.

It can also optimize the administration of various first-line drugs, including AKT inhibitors VIII Imatinib, Crizotinib, Saracatinib, Erlotinib, Dasatinib, Rapamycin, Roscovitine and Shikonin in BC patients. Finally, we employed machine learning techniques to construct a multi-omics prediction model(Risklight),with an area under the feature curve (AUC) of up to 0.89. With the help of CAG_score and Risklight, we reveal the signature of cholesterol homeostasis-related genes for angiogenesis, immune responses, and the therapeutic response in breast cancer, which contributes to precision medicine and improved prognosis of BC.

Additionally, by applying our prediction model, we segregated PC patients into high-risk and low-risk groups, identifying potential benefits of cisplatin, docetaxel, pazopanib, midostaurin, epothilone.B, thapsigargin, bryostatin.1, and AICAR for high-risk PC patients, and metformin, roscovitine, salubrinal, and cyclopamine for those in the low-risk group. This study unveils IFN-γGs related molecular subsets in pancreatic cancer for the first time, shedding light on the pivotal role of IFN-γGs in the progression of PC. Furthermore, we establish an IFN-γGs related prognostic model for predicting the survival of PC, offering a theoretical foundation for exploring the precise mechanisms of IFN-γGs in PC.

So far, several drugs or biomolecules have been discovered that can target EBV-encoded products for treatment, such as Silvestrol, affinity toxin, roscovitine, H20, H31, curcumin, thymoquinone, and ribosomal protein L22...Additionally, some promising findings in the fields of vaccines, immunological, and cellular therapies have been established. In this review, we mainly summarise the function of drugs mentioned above and unique mechanisms, hoping that we can help giving insight to the design of drugs for the treatment of EBV-associated diseases.

Inhibitors of proteostasis and the MEK-ERK pathway, as well as the pan-CDK inhibitors, flavopiridol, and seliciclib, were potently synergistic with TAP20 in two cell lines. However, TAP20 alone was sufficient to restrict invasion at concentrations well below its growth-inhibitory IC. We conclude that GCN2 inhibition can be further explored in vivo as a cancer target.

Compounds 4b, 4c, and 6a also showed promising dual EGFR and CDK-2 inhibition activities, particularly 6a was the most effective (IC = 19.6 and 87.9 nM, respectively), better than Erlotinib and Roscovitine. Compound 6a treatment induced EGFR and CDK-2 enzyme inhibition by 97.18% and 94.11%, respectively, at 10 μM (the highest concentration). Compound 6a notably induced cell apoptosis in MCF-7 cells, increasing the cell population by total apoptosis 43.3% compared to 1.29% for the untreated control group, increasing the cell population at the S-phase by 39.2% compared to 18.6% (control).

Moreover, FD2056 showed more efficacious anti-TNBC activity than the corresponding drugs BKM120 and CYC202 at an oral dose of 15 mg/kg in the MDA-MB-231 xenograft model, inhibiting tumor growth by 43% with no observable toxic effects. All these results suggest that FD2056 has potential for further development as a promising anticancr compound, and co-targeting PI3K and CDK2 pathways may provide an alternative therapeutic strategy for the treatment of TNBC.

The new saponin (1) exhibited promising cytotoxicity with IC values of 3.5 and 5.52 μM on A549 and PC-3 cancer cell lines, respectively, compared to doxorubicin with IC values of 9.44 and 11.39 μM on A549 and PC-3 cancer cell lines, respectively...Compound 1 exhibited remarkable CDK-2 target inhibition by 96.2% with an IC value of 117.6 nM compared to Roscovitine. The molecular docking study further confirmed the binding affinity of compound 1 as CDK2 and Bcl2 inhibitors that led to apoptosis induction in A549 cancer cells. Hence, this study highlights the importance of compound 1 in the design of a new anticancer agent with specific mechanisms.

The candidate 8c exhibited more potent activity (10.10- and 2.27-fold) than the standard drug roscovitine (IC  = 1.91 ± 0.17 µM (MCF-7) and 2.36 ± 0.21 µM (HepG2)). Compound 8c was investigated for epidermal growth factor receptor (EGFR) inhibition; it exhibited promising IC values of 96.6 nM compared with 67.3 nM for erlotinib...Additionally, for apoptosis induction of compound 8c in MCF-7, it upregulated the expression levels of proapoptotic genes for P53, Bax, caspases-3, 8, and 9 at up to 6.18, 4.8, 9.8, 4.6, 11.3 fold-change, respectively, and downregualted the level of the antiapoptotic gene for Bcl-2 by 0.14-fold. Finally, a molecular docking study of the most active compound 8c highlighted a good binding affinity with Lys89 as the key amino acid for CDK-2 inhibition.

Small-molecule drugs panobinostat, oxaliplatin, ixabepilone, and seliciclib were significantly associated with ADH1B. Our study provides ADH1B as a key afatinib-related gene, which is associated with the immune microenvironment and can be used to predict the prognosis of LIHC. It is also a potential target of candidate drugs, sharing a promising approach to the development of novel drugs for the treatment of LIHC.

CENPO was found to be positively associated with the expression levels of immune checkpoints and drug IC50 value (Roscovitine and TGX221), but negatively associated with the fraction levels of several immature cells and drug IC50 value (CCT018159, GSK1904529A, Lenaildomide, and PD-173074). The removal of CENPO significantly suppressed metastasis and induced arrest and apoptosis of LUAD cells. The involvement of CENPO in the immunosuppression of LUAD provides a prognostic signature for LUAD patients.

Compounds 7b and 12f displayed enhanced activity (half-maximal inhibitory concentration [IC ] = 0.46 and 0.27 µM, respectively) in comparison to the standard roscovitine (IC  = 1.41 ± 0.03 µM), in addition to, cell cycle arrest at S phase and G1/S transition phase in MCF7 cells treated with both compounds, respectively...Molecular docking studies demonstrated the plausible interaction patterns of the most potent derivatives 17b and 12f in the CDK2 binding pocket and the spiro-oxindole 16a with p53-MDM2 complex, respectively. Consequently, the new chemotypes 7b, 12f, and 16a can be presented as promising antitumor hits for further studies and optimization.

Compounds 5 and 8 were shown to be the most effective, with half-maximal inhibitory concentration (IC ) values between 5.73 and 9.11 µM, which are on the level with doxorubicin. In addition, compounds 5 and 8 showed strong anti-CDK2 action (IC  = 0.112 and 0.18 µM, respectively) comparable to roscovitine (IC  = 0.127 µM). Moreover, the docking result demonstrated that derivatives 5 and 8 fit into the CDK2 active site in the proper orientation.

P276-00 (also known as riviciclib), roscovitine and UCN-01 on CRC cell lines of varied genetic background were delineated. No abstract available

We found that less-selective CDKIs, including flavopiridol, roscovitine, dinaciclib, and SNS-032, induced DR5 via p73-mediated transcriptional activation...CDKIs strongly synergized with 5-fluorouracil (5-FU), the most commonly used CRC chemotherapy agent, in vitro and in vivo to promote growth suppression and apoptosis, which required DR5 and p73. Together, these findings indicate p73-mediated DR5 induction as a potential tumor suppressive mechanism and a critical target engaged by different CDKIs in potentiating therapy-induced apoptosis in CRC cells. These findings help better understand the anticancer mechanisms of CDKIs and may help facilitate their clinical development and applications in CRC.

In vitro pretreatment with the CDK inhibitor, seliciclib, before irradiation significantly decreased the survival of A549 and H520 cells in a dose-dependent manner...An in vivo xenograft model showed that the combination of CDK inhibition and ionizing radiation delayed xenograft tumor growth, and increased the proportion of cleaved PARP-1- and cleaved caspase-3-positive cells, compared to either treatment alone. We provide preclinical tumoricidal evidence that the combination of CDK inhibition and ionizing radiation is an efficacious treatment for lung cancer.

Specifically, patients with high NRG score may benefit from treatment with anti-EGFR and CDK2 inhibitors, including erlotinib and roscovitine. The NPM1 and FLT3 mutant cell lines undergo alterations after multiple drug treatments. Our established NRG signature and scoring highlight its vital clinical significance, emphasize the inevitability of stratifying treatment for different mutation subtypes and provide new ideas to guide personalized immunotherapy strategies for AML patients.

We looked for the role of USP8 mutations or a changed p27 level in the response to palbociclib, flavopiridol and roscovitine in vitro using murine corticotroph AtT-20/D16v-F2 cells. Overexpression of mutated Usp8 in the cells did not affect the expression of p27 nor the response to the inhibitors. Downregulating or upregulating p27 expression in AtT-20/D16v-F2 cells also did not affect treatment response.

Using available genetic atlas data, potential drug candidates for treatment of PDAC were identified based on differentially expressed genes, protein interaction analysis and connectivity mapping. These results may help focus efforts on identifying targeted agents with potential therapeutic efficacy for evaluation in prospective clinical trials of patients with PDAC.

Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). The best combination effects were achieved when both drugs were maintained together. Altogether, this study provides a rationale for the clinical development of fadraciclib in CLL, either alone or in combination with a Bcl-2 antagonist.

These included pan-CDK family inhibitors alvocidib, CGP60474, and roscovitine-derived CR8. Conclusion We provide evidence that high-content drug screening in a co-culture system is an effective strategy to identify clinically-relevant novel and emerging therapeutic targets in high-risk ALL. Our analyses promote a strong rationale for exploring the targeting of CDKs as a potential pan-effective approach in high-risk adult ALL.

In LCC1 and LCC9 cell lines, loss of estrogen sensitivity was accompanied by loss of growth response to transforming growth factor alpha (TGFα), heregulin-beta and pertuzumab. Multiple changes occur with progression of endocrine resistance in this model with AKT activation contributing to E insensitivity and loss of ERα(Ser118) phosphorylation being associated with full resistance. Cell cycle regulation is modified in endocrine-resistant breast cancer cells, and seliciclib is effective in both endocrine-sensitive and resistant diseases.

OncoTreat analysis predicted sensitivity to camptothecin, seliciclib, galunisertib, and rigosertib in both fibroblast- and chondroblast-like subpopulations. In conclusion, using network-based systems biology approaches in OS, we identified pharmacologically accessible MR subtypes differentiating survival at the bulk tissue level, and defining three distinct tumor subpopulations at the single-cell level with unique predicted drug sensitivities.

GSs with poor survival were mainly infiltrated by mesenchymal stem cells (MSCs) and astrocyte, and were more sensitive to gefitinib and roscovitine. Among GSs, three hub genes KRT8, NGFR, and TCEA3, were screened and validated to potentially play feasible oncogenic roles in GBM. Construction of lncRNAs risk model and identification of GBM subtypes based on 17 irlncRNAs, which suggesting that irlncRNAs had the promising potential for clinical immunotherapy of GBM.

P1, N=103, Completed, Cyclacel Pharmaceuticals, Inc. | Recruiting --> Completed

This study demonstrated the correlations between cellular senescence patterns and tumor immune landscape in LUAD, which enhanced our understanding of the tumor immune microenvironment and provided new insights for improving the outcome of immunotherapy for LUAD patients.

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.

Docking to CDK2 ATP binding site revealed similar interactions as the co-crystallized ligand R-Roscovitine (PDB code; 3ddq). These findings present compounds 8a-c as promising anti-proliferative agents.

The inhibition of multiple centrosomes accomplished by treating cells with either roscovitine or centrinone or through the overexpression of NR5A1/SF-1 alleviated ETO-induced senescence, suggesting that ETO triggered senescence via multiple centrosomes. Thus, ETO activated the DNA-PK-Chk2 cascade to facilitate autophagy. The activated autophagy further induced multiple centrosomes and primary cilia followed by triggering senescence.

All the former mechanisms may become interesting therapeutic targets for CTs, aside from temozolomide, currently used for aggressive tumors. Potential therapeutic agents are EGFR inhibitors such as gefitinib and lapatinib, the purine analog R-roscovitine by dissociation of CDK2/Cyclin E complex, the HSP90 inhibitor silibinin (novobiocin), to reduce resistance to glucocorticoid-mediated negative feedback, and BRAF inhibitors vemurafenib and dabrafenib in BRAF V600E positive tumors. This review summarizes the molecular mechanisms related to CTs tumorigenesis, their diagnostic approach, and provides an update of the potential novel therapies, from the lab bench to the clinical translation.

The highest MCF7 growth inhibition activity was attained via compounds 4f and 7e (IC = 1.29 and 0.93 μM, respectively), while compounds 5b and 7f were the most active ones against HepG2 (IC = 1.57 and 1.33 μM, respectively) compared to doxorubicin (IC = 1.88 and 7.30 μM, respectively)...Docking in CDK2 ATP binding site, co-crystallized with R-Roscovitine, demonstrated analogous interactions and comparable binding energy with the native ligand. 2D QSAR sighted the possible structural features governing the CDK2 inhibition activity elicited by the studied pyrazolo&lsqb;3,4-b]pyridines. These findings present compounds 4f, 5b, and 7f as selective CDK2 inhibitors with promising antiproliferative activity against MCF7 and HepG2 cancer cells.

Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546).

Moreover, a decrease in beclin-1, LC3A, and LC3B were observed in two cell lines after treatment with novel compounds. This study showed that novel 7-methyl-5-phenyl-pyrazolo&lsqb;4,3-e]tetrazolo&lsqb;4,5-b]&lsqb;1,2,4]triazine derivatives might be a potential strategy in colon cancer treatment.

Treatment with hypothermia, or a selective CDK4 inhibitor, or roscovitine (CDK5 inhibitor) prevented MPP-induced mitochondrial fission, upregulation of mitochondrial fission protein dynamin-related protein 1 (Drp1), and neuron death...These results elucidate that hypothermia may inhibit CDK4 and CDK5 activation by upregulating p27 and p35 expression to prevent Drp1-dependent mitochondrial fission and neuron loss after MPP treatment. CDK4 and CDK5 inhibition imitates the neuroprotective functions of hypothermia as a potential therapy for PD.

Inhibition of CDK5 with myricetin or roscovitine, a CDK5 inhibitor attenuates thapsigargin induced p66Shc serine 36 phosphorylation and also reduced mitochondrial dysfunction by decreasing mitochondrial ROS and caspase-3 activation...Myricetin blocked thapsigargin induced CDK5-p66Shc signalosome formation and prevented pancreatic beta cell dysfunction. In this study, we demonstrated for the first time that thapsigargin initiated CDK5-p66Shc signalosome mediates the pancreatic beta cell dysfunction and myricetin protects the pancreatic beta cells through the inhibition of CDK5-p66Shc signalosome.

The treatment of human cholangiocarcinoma cell lines (CCKS‑1, TFK‑1 and HUCCT‑1) with the multi‑CDK inhibitor roscovitine decreased p‑CDK1 expression, inhibited cell proliferation, arrested the cell cycle at the G1 or G2/M phase, and significantly inhibited carcinoma cell invasion...These results demonstrated the potential of the CDK pathway involving CDK1 as a therapeutic target for cholangiocarcinoma. Furthermore, the immunohistochemical expression of p‑CDK1 may be a useful prognostic marker of cholangiocarcinoma.

P1, N=0, Withdrawn, M.D. Anderson Cancer Center | N=40 --> 0