Expanding the arsenal of FGFR inhibitors: A novel chloroacetamide derivative as a new irreversible agent with anti-proliferative activity against FGFR1-amplified lung cancer cell lines

Fibroblast Growth Factor Receptors (FGFR1-4) have a critical role in the progression of several human cancers, including Squamous Non-Small-Cell Lung Cancer (SQCLC). Both non-selective and selective reversible FGFR inhibitors are under clinical investigation for the treatment of patients with tumors harboring FGFR alterations. Despite their potential efficacy, the clinical development of these drugs has encountered several challenges, including toxicity, and the appearance of drug resistance. Recent efforts have been directed at development of irreversible FGFR inhibitors, which have the potential to exert superior anti-proliferative activity in tumors carrying FGFR alterations. With this in mind, we synthetized, and investigated a set of novel inhibitors possessing a warhead potentially able to covalently bind a cysteine in the P-loop of FGFR. Among them, the chloroacetamide UPR1376 resulted able to irreversible inhibit FGFR1 phosphorylation in FGFR1 over-expressing cells generated from SQCLC SKMES-1 cells. In addition, this compound inhibited cell proliferation in FGFR1-amplified H1581 cells with a potency higher than the reversible inhibitor BGJ398 (infigratinib), while sparing FGFR1 low-expressing cells. The anti-proliferative effects of UPR1376 were demonstrated in both 2D and 3D systems and were associated with the inhibition of MAPK and AKT/mTOR signaling pathways. UPR1376 inhibited cell proliferation also in two BGJ398-resistant cell clones generated from H1581 by chronic exposure to BGJ398, although at concentrations higher than those effective in the parental cells, likely due to the persistent activation of the MAPK pathway associated to NRAS amplification. Combined blockade of FGFR1 and MAPK signaling, by UPR1376 and trametinib respectively, significantly enhanced the efficacy of UPR1376, providing a means of circumventing resistance to FGFR1 inhibition. Our findings suggest that the insertion of a chloroacetamide warhead on a suitable scaffold, as exemplified by UPR1376, is a valuable strategy to develop a novel generation of FGFR inhibitors for the treatment of SQCLC patients with FGFR alterations

Hyperosmotic stress response: comparison with other cellular stresses

Cellular responses induced by stress are essential for the survival of cells under adverse conditions. These responses, resulting in cell adaptation to the stress, are accomplished by a variety of processes at the molecular level. After an alteration in homeostatic conditions, intracellular signalling processes link the sensing mechanism to adaptive or compensatory changes in gene expression. The ability of cells to adapt to hyperosmotic stress involves early responses in which ions move across cell membranes and late responses characterized by increased synthesis of either membrane transporters essential for uptake of organic osmolytes or of enzymes involved in their synthesis. The goal of these responses is to return the cell to its normal size and maintain cellular homeostasis. The enhanced synthesis of molecular chaperones, such as heat shock proteins, is another important component of the adaptive process that contributes to cell survival. Some responses are common to different stresses, whereas others are specific. In the first part of the review, we illustrate the characteristic and specific features of adaptive response to hypertonicity; we then describe similarities to and differences from other cellular stresses, such as genotoxic agents, nutrient starvation and heat shock

Clinical perspective for irreversible tyrosine kinase inhibitors in cancer

Irreversible inhibitors provide potent and selective inhibition of tyrosine kinase enzymes. Use of such inhibitors has proved promising in overcoming the tumor resistance encountered with reversible tyrosine kinase inhibitors. Irreversible inhibitors inactivate their protein target through covalent interaction with a nucleophilic cysteine residue within the nucleotide binding pocket of the kinase domain. Different irreversible tyrosin kinase inhibitors directed against epidermal growth factor receptor (EGFR), Bruton's tyrosine kinase (BTK), vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor tyrosine kinase (FGFR) have been developed and some of them have been employed clinically as anticancer agents. This review focuses on recent preclinical and clinical progress with currently available irreversible tyrosine kinase inhibitors. The chemical structures of the candidates, structure-activity relationships, biological activities and results of current clinical investigations are describe