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This study provides a comprehensive computational procedure for the discovery of novel urea-based antineoplastic kinase inhibitors while focusing on diversification of both chemotype and selectivity pattern. It presents a systematic structural analysis of the different binding motifs of urea-based kinase inhibitors and the corresponding configurations of the kinase enzymes. The computational model depends on simultaneous application of two protocols. The first protocol applies multiple consecutive validated virtual screening filters including SMARTS, support vector-machine model (ROC = 0.98), Bayesian model (ROC = 0.86) and structure-based pharmacophore filters based on urea-based kinase inhibitors complexes retrieved from literature. This is followed by hits profiling against different extended electron distribution (XED) based field templates representing different kinase targets. The second protocol enables cancericidal activity verification by using the algorithm of feature trees (Ftrees) similarity searching against NCI database. Being a proof-of-concept study, this combined procedure was experimentally validated by its utilization in developing a novel series of urea-based derivatives of strong anticancer activity. This new series is based on 3-benzylbenzo[d]thiazol-2(3H)-one scaffold which has interesting chemical feasibility and wide diversification capability. Antineoplastic activity of this series was assayed in vitro against NCI 60 tumor-cell lines showing very strong inhibition of GI(50) as low as 0.9 uM. Additionally, its mechanism was unleashed using KINEX™ protein kinase microarray-based small molecule inhibitor profiling platform and cell cycle analysis showing a peculiar selectivity pattern against Zap70, c-src, Mink1, csk and MeKK2 kinases. Interestingly, it showed activity on syk kinase confirming the recent studies finding of the high activity of diphenyl urea containing compounds against this kinase. Allover, the new series, which is based on a new kinase scaffold with interesting chemical diversification capabilities, showed that it exhibits its "emergent" properties by perturbing multiple unexplored kinase pathways.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502486 | PMC |
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049284 | PLOS |
J Int Med Res
December 2024
Department of Urology, Shaoxing People's Hospital, Shaoxing, Zhejiang, China.
renal transplant carcinoma, especially in the context of bilateral renal carcinoma, is rare and often presents as small, low-grade papillary renal cell carcinoma (RCC). There is currently no consensus or effective treatment for advanced metastatic RCC after kidney transplantation. A 40-year-old man developed renal transplant carcinoma with venous thrombus and lung metastases 13 years after transplantation.
View Article and Find Full Text PDFThyroid
December 2024
Laboratory of Endocrinology and Receptor Biology, Bethesda, Maryland, USA.
Thyrotropin receptor (TSHR) and insulin-like growth factor 1 receptor (IGF-1R) have been shown to crosstalk in primary cultures of human thyrocytes (hThyros) and Graves' orbital fibroblasts. The phenomenon of TSHR/IGF-1R crosstalk has been largely studied in the pathogenesis of thyroid eye disease (TED) in human orbital fibroblasts. Here, we investigated the effects of inhibiting the IGF-1R-mediated contribution to crosstalk by linsitinib (Lins), a small-molecule IGF-1R kinase inhibitor, on TSH-induced regulation of thyroperoxidase (TPO) and thyroglobulin (TG) mRNAs and proteins in hThyros and on TPO and TG mRNAs and free thyroxine (fT4) levels in mice.
View Article and Find Full Text PDFCell Oncol (Dordr)
December 2024
Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Background: Hepatocellular carcinoma (HCC) remains a significant global health challenge with limited treatment options. Lenvatinib, a tyrosine kinase inhibitor, has shown promise but is often undermined by the development of drug resistance.
Methods: Utilizing high-throughput sequencing, we investigated the molecular mechanisms underlying lenvatinib resistance in HCC cells, with a focus on metabolic pathways.
Int Urol Nephrol
December 2024
Department of Urology, Institute of Urology, West China Hospital, Sichuan University, No.37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan, People's Republic of China.
Purpose: To evaluate the efficacy and safety of extended immunotherapy in first-line immune checkpoint inhibitors (ICIs)-tyrosine kinase inhibitors (TKIs) combination treatment for advanced renal cell carcinoma (RCC).
Patients And Methods: We retrospectively analyzed data from patients with advanced RCC who received first-line ICIs-TKIs combination treatment at West China Hospital of Sichuan University between October 2018 and July 2024. Patients who are assessed as having a disease control status after 2 years of continuous treatment will continue to receive immune checkpoint inhibitors until the inhibitors are discontinued due to disease progression or death.
Hum Cell
December 2024
Department of Gynecology, Jiangyin Hospital Affiliated to Nantong University, Wuxi, 214400, Jiangsu, People's Republic of China.
Curzerenone is a major component of the traditional herbal medicine Curcumae Rhizoma with potential cancer-suppressing effects. This study aims to investigate the treatment effect of Curzerenone on cervical cancer cells and the underpinning mechanism. HeLa and SiHa cells were treated with Curzerenone.
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