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Renal cell cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Dovitinib, another VEGFR and PDGFR rTKI also demonstrates activity against fibroblast growth factor receptor (FGFR), a potential mediator of tumour resistance to current VEGF directed therapy. Early phase data is encouraging and a recent clinical trial (GOLD) evaluating Dovitinib against Sorafenib, following failure of both VEGF- and mTOR-directed therapy, has recently completed accrual.119
Identification of new benzimidazole-triazole hybrids as anticancer agents: multi-target recognition, in vitro and in silico studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Dina I. A. Othman, Abdelrahman Hamdi, Samar S. Tawfik, Abdullah A. Elgazar, Amany S. Mostafa
As shown in Figure 1, Bendamustine (I) is a nitrogen mustard benzimidazole based alkylating agent used in the treatment of chronic lymphoma6. Dovitinib (II) is an orally active benzimidazole-quinolinone hybrid with potential antineoplastic activity as multiple receptor tyrosine kinases’ (RTKs) inhibitor. It strongly targets fibroblast growth factor receptor-1 (FGFR-1) (IC50 = 8 nM), vascular endothelial growth factor receptor-2 (VEGFR-2) (IC50 = 13 nM), and other RTKs involved in tumour growth and angiogenesis, like FGFR-3, VEGFR-1, VEGFR-3, and PDGFR. It also targets Topoisomerase II (Topo II) enzyme with IC50 of 13 μM8. Dovitinib has been exclusively in-licensed worldwide by Novartis, who has completed phase-III study against renal cell carcinoma (RCC), in addition to several promising phase-II studies against liver, breast, endometrial cancer, and gastrointestinal stromal tumour10–12.
In Vitro Effect of Dovitinib (TKI258), a Multi-Target Angiokinase Inhibitor on Aggressive Meningioma Cells
Published in Cancer Investigation, 2020
Arabinda Das, Jaime L. Martinez Santos, Mohammed Alshareef, Guilherme Bastos Ferreira Porto, Libby Kosnik Infinger, William A. Vandergrift, Scott M. Lindhorst, Abhay K. Varma, Sunil J. Patel, David Cachia
Dovitinib (TKI258; formerly CHIR-258) is an investigational drug developed by Novartis, which has shown a dose- and exposure-dependent inhibition of RTKs, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), stem cell factor (c-KIT), Flt3 and colony-stimulating factor-1 (CSF-1) expressed tumor in several preclinical models such as advanced breast cancer, hepatocellular carcinoma, and endometrial cancer (7–11). This action resulted in a reduction in cell proliferation, migration, angiogenesis, vascular density, and the induction of tumor cell death. Due to its high activity and oral bioavailability, Dovitinib is now in phase I/II/III trial for renal cell carcinoma, HR+/HER2− FGF pathway-amplified advanced breast cancer, relapsed multiple myeloma and urothelial cancer (7–11). Several clinical trials have been conducted to delineate the safety, efficacy, and pharmacokinetics of Dovitinib (NCT00958971, NCT00790426).
Targeting FGFR in bladder cancer: ready for clinical practice?
Published in Acta Clinica Belgica, 2020
Stijn De Keukeleire, Daan De Maeseneer, Celine Jacobs, Sylvie Rottey
To assess the pharmacodynamic and clinical activity of FGFR inhibitors several (early phase) clinical trials have been completed or are still ongoing. In 2014, Milowsky et al. [30] performed a phase II, multicentre study to investigate the safety and efficacy of dovitinib, a non-selective multi-targeted TKI, in patients with advanced or metastasized UC. Patients were screened for FGFR3 mutations using Sanger sequencing stratified according to mutational status. Eventually, 31 patients had FGFR3 wild-type expression, 12 patients were diagnosed with mutated FGFR3, and 1 patient had an unknown mutation. All patients were treated with dovitinib for a median duration of 7.5 weeks (0.4–58 weeks). Although tolerance was well accepted, clinical efficacy was extremely limited, with only one FGFR3wt who had PR (partial response). Eventually, early discontinuation of the trial was necessary due to low response of dovitinib [30].