Search results for "FGFR4"

Design, synthesis and biological evaluation of new anticancer drugs: FGFR inhibitors

2021

Fibroblast growth factor receptors (FGFRs) constitute a family of tyrosine kinases receptors (RTKs) that exert pivotal physiological functions in human embryonic and adult tissues. Hyperactivated FGFR signaling drives tumorigenesis in multiple cancer types, including lung and brain cancers. Great effort has been laid on the development of new compounds that specifically target the FGFR axis. However, cancer cell- based and microenvironmental resistance mechanisms against FGFR inhibitors often arise and are currently poorly understood. Furthermore, FGFR-targeted therapy often presents different side effects, e due to the broad biological spectrum of the FGFR signaling axis as well as to its …

The differential diagnoses of uterine leiomyomas and leiomyosarcomas using DNA and RNA sequencing.

2019

BACKGROUND: Although uterine leiomyomas and leiomyosarcomas are considered biologically unrelated tumors, they share morphologic and histologic characteristics that complicate their differential diagnosis. The long-term therapeutic option for leiomyoma is laparoscopic myomectomy with morcellation, particularly for patients who wish to preserve their fertility. However, because of the potential dissemination of undiagnosed or hidden leiomyosarcoma from morcellation, there is a need to develop a preoperative assessment of malignancy risk. OBJECTIVE: Through an integrated comparative genomic and transcriptomic analysis, we aim to identify differential genetic targets in leiomyomas vs leiomyosa…

BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer

2022

The heterogeneous therapy response observed in colorectal cancer is in part due to cancer stem cells (CSCs) that resist chemotherapeutic insults. The anti-apoptotic protein BCL-XL plays a critical role in protecting CSCs from cell death, where its inhibition with high doses of BH3 mimetics can induce apoptosis. Here, we screen a compound library for synergy with low-dose BCL-XL inhibitor A-1155463 to identify pathways that regulate sensitivity to BCL-XL inhibition and reveal that fibroblast growth factor receptor (FGFR)4 inhibition effectively sensitizes to A-1155463 both in vitro and in vivo. Mechanistically, we identify a rescue response that is activated upon BCL-XL inhibition and leads …

Progettazione e sintesi di nuovi complessi metallici potenziali inibitori di FGFR4

2019

I pathways di segnalazione che coinvolgono il recettore del fattore di crescita dei fibroblasti 4 (FGFR4) risultano alterati in varie tipologie di tumori [1] ed è stato dimostrato come l’interruzione della segnalazione FGF19/FGFR4 interrompa la proliferazione e induca l’apoptosi delle cellule tumorali, offrendo grandi promesse terapeutiche. [2-4] Allo scopo d’individuare nuovi leganti FGFR4, sono stati effettuati degli studi di modellistica molecolare (Fig. 1) che, riferendosi alla struttura del ponatinib, noto inibitore di FGFR4, [5] il cui utilizzo è ostacolato dall’elevata lipofilia e da effetti secondari, hanno consentito di generare una “Drug Discovery Library” di oltre 30 nuovi potenz…

Design of copper(II) complexes as potential anticancer prodrugs

The fibroblast growth factor receptors (FGFR) are tyrosine kinases that are present in many types of endothelial and tumor cells and play an important role in cell growth, survival, and migration as well as in maintaining tumor angiogenesis (1). FGFR genetic alterations are frequently observed in cancer, suggesting that FGFR inhibition may be a promising therapy in patients harboring these lesions (2). In particular, molecules with structural properties similar to Ponatinib, a known inhibitor of FGFR, that shows a selective interaction for the ATP binding site of the isoform 4 of these receptors (FGFR4), are being considered. Molecular modeling studies have been conducted to design novel po…