ARQ 087 is a novel, ATP competitive, small molecule, multi-kinase inhibitor with potent in vitro and in vivo activity against FGFR-addicted cell lines and tumors

ARQ 087 is a novel, ATP competitive, small molecule, multi-kinase inhibitor with potent in vitro and in vivo activity against FGFR-addicted cell lines and tumors. demonstrated in the pathogenesis of GC, via the accumulation of nuclear YAP1 in an uncontrollable manner [10,11,12]. Moreover, recent studies have further uncovered the emerging functions of fibroblast growing factors LY2140023 (LY404039) (FGFs) and their receptors (FGFRs) in the carcinogenesis of some GC subtypes, owing to their molecular characteristics [13]. It has been well documented that this FGF and FGFR families are important regulators for biological development [14,15]. Aberration of FGF-FGFR signaling substantially results in skeletal disorders as well as malignancy development, including GC [16]. Since genetic aberrations of FGFR2 have been recently defined, it serves as a diagnostic marker and clinical drug target for GC [17,18,19]. However, development of FGFR2-targeted therapy has been largely decelerated due to recently reported disadvantages. Thus, further investigation of the FGF-FGFR must be continued in order to identify drug targets for GC therapy. This review aims to summarize the updated discoveries and discuss the further potential customers of FGF-FGFR signaling in GC pathogenesis and therapy development. 2. Emerging Role of FGF-FGFR in Solid Tumors 2.1. FGF Family Induces Tumor Growth FGFRs belong to the receptor tyrosine kinases LY2140023 (LY404039) (RTKs) superfamily. Most of the RTKs are membrane receptors with high affinity to multiple growth factors, cytokines, and hormones, and they contain intracellular domains with tyrosine kinase activity. Canonically, FGFRs are monomers in their inactivation state. Dimerization of the intracellular part occurs after binding with their ligand FGFs. Functional binding of FGF and FGFR leads to cross-phosphorylation and activation of the receptor. Activated FGFRs then transduce biochemical signals into cytosolic activities [20]. Indeed, the FGF family comprises 22 secreted factors that are generally divided into seven subgroups in terms of their phylogenetic relation, homology, and biochemical function [21]. As reported, five FGF subfamilies are released in paracrine LY2140023 (LY404039) and autocrine manners, including FGF1 (FGF1, FGF2), FGF4 (FGF4, FGF5, FGF6), FGF7 (FGF3, FGF7, FGF10, FGF22), FGF8 (FGF8, FGF17, FGF18), and FGF9 (FGF9, FGF16, FGF20). In contrast, the FGF15 (FGF15, FGF19, FGF21, FGF23) subfamily is usually secreted through endocrine glands as a hormone for metabolic modulation with – and -Klotho family proteins. Nevertheless, there are intracellular FGFs (FGF11, FGF12, FGF13, FGF14) that lack secretory N-terminal peptides, Rabbit Polyclonal to ADCK5 which execute their functions impartial of FGFRs [22]. FGFs not only show regulatory functions in cell fate and survival, but also exerts biological functions in tissue regeneration LY2140023 (LY404039) and repair [23,24]. In the last few decades, clinical reports have highlighted the importance of FGFs in tumorigenesis, including excessive cell growth and angiogenesis. For example, basic fibroblast growth factor (bFGF) promotes angiogenesis for hepatoma progression [25], and a follow-up study suggested serum bFGF as a biological indication for invasive and recurrent hepatocellular carcinoma (HCC) [26]. The clinical significance of bFGF was first recognized in patients who received surgical removal of colorectal malignancy (CRC) at serological and pathological levels, where expression of bFGF indicated the independency in lymphatic invasion [27]. In addition, amplification ranked 10% in human malignancies, as overproduction of FGFs enables the communication between epithelial cells and stromal cells in the tumor microenvironment for tumorigenesis [28,29]. 2.2. FGFR Family Drives Oncogenesis 2.2.1. Functional Structures of FGFR Interestingly, FGF ligands interact with only four FGFRs (FGFR1C4), which are highly conserved in mammals, although FGFs harbor many family members. In general, FGFRs can be classified into three major domains based on their location relative to the cell membrane: (1) a ternary extracellular immunoglobulin LY2140023 (LY404039) (Ig) (domain name I, II, III) that is in charge of binding with ligands; (2) a signal-pass transmembrane helix that functions as a connection; and (3) an intracellular tyrosine kinase (TK) that conveys the signals [30,31]. Generally speaking, the extracellular part of the FGFR provides binding sites for ligand binding, while the intracellular part is responsible for potentiating the relevant signaling pathways. Between the extracellular domains I and II, there is an acidic box region for the FGFR to interact with some molecules other.