Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors

Abstract

Fibroblast growth factor receptors (FGFR1-4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2). In in vivo studies, 9g displayed clear antitumor activities in NCI-H1581 and SNU-16 xenograft mice models. Additionally, the diluting method confirmed the irreversible binding of 9g to FGFR.

TAS‐120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure

“…Irreversible inhibitors have most often used a reactive acrylamide group to target an unpaired cysteine residue in the kinase active site by forming a covalent bond through a Michael addition reaction. In the FGFRs, a cysteine residue at the tip of the P‐loop can be targeted (numbered Cys488 in FGFR1), and is conserved across all four receptors (FGFR1–4) . In FGFR4, an alternative active site cysteine (numbered Cys552 in FGFR4) is modified by a series of recently synthesised and highly selective compounds .…”

“…[9,10,16] Irreversible inhibitors have the potential to be highly selective because they target au nique residue of as pecific kinase by design. [17][18][19] This specific and irreversible behaviour allows inhibition even at high levels of intracellularA TP,w hich provides al ower dosing requirement and ad ecreasedl ikelihood of off-target toxic side effects. However,i rreversible inhibitors were avoidedf or somet ime, as ar esult of toxicities potentially linked to undesirable immunological responses and indiscriminate modificationo fr andom cellular targets by the highlyr eactive electrophilic groupsi nvolved.…”

“…In the FGFRs, ac ysteiner esidue at the tip of the P-loop can be targeted (numbered Cys488 in FGFR1), and is conserved across all four receptors (FGFR1-4). [17,22] In FGFR4,a na lternative active site cysteine (numbered Cys552 in FGFR4)i sm odified by as eries of recently synthesised and highly selective compounds. [23] FIIN-1 (1)w as the first reported irreversible FGFR inhibitor developed using as tructure-guided approachu sing reversiblei nhibitor PD173074 as al ead pharmacophore.…”

Aortic dissection in a patient treated with anlotinib for metastatic lung squamous cell carcinoma

“…The aorta is comprised of the tunica intima, tunica media, and tunica adventitia . Vascular endothelial growth factor receptor (VEGFR), platelet‐derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR1‐4) are expressed in vascular endothelial cells and maintain normal vascular endothelial development and homeostasis . Anlotinib is an anti‐angiogenic drug that targets VEGFR, PDGFR, FGFR1‐4, c‐Kit, and other kinases and has been approved for the treatment of advanced non‐small cell lung cancer (NSCLC) .…”

C11, a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor, suppresses breast cancer metastasis and angiogenesis

“…Great efforts have been directed toward blockade of FGF/FGFR signaling as an antitumor therapeutic approach [9][10][11]. Present FGFR inhibitors can be divided into two groups: nonselective FGFR TKIs and selective FGFR TKIs.…”