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Fibroblast Growth Factor Receptors (FGFRs): Structures and Small Molecule Inhibitors

Shuyan Dai, Zhan Zhou, Zhuchu Chen and 2 more

Cells · 2019 · Review · CC BY

doi:10.3390/cells8060614

Abstract

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases expressed on the cell membrane that play crucial roles in both developmental and adult cells. Dysregulation of FGFRs has been implicated in a wide variety of cancers, such as urothelial carcinoma, hepatocellular carcinoma, ovarian cancer and lung adenocarcinoma. Due to their functional importance, FGFRs have been considered as promising drug targets for the therapy of various cancers. Multiple small molecule inhibitors targeting this family of kinases have been developed, and some of them are in clinical trials. Furthermore, the pan-FGFR inhibitor erdafitinib (JNJ-42756493) has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic or unresectable urothelial carcinoma (mUC). This review summarizes the structure of FGFR, especially its kinase domain, and the development of small molecule FGFR inhibitors.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

The human fibroblast growth factor receptor (FGFR) family consists of four members: FGFR1 to FGFR4. Despite being encoded by separate genes, the four members share high homology, with their sequence identity varying from 56% to 71%. Similar to other receptor tyrosine kinases (RTKs), FGFRs are expressed on the cell membrane and can be stimulated and activated by extracellular signals. The native ligand of FGFRs is fibroblast growth factors (FGFs). The binding of FGFs drives the dimerization of FGFRs; subsequently, a transautophosphorylation event of the intracellular kinase domain is induced, followed by the activation of downstream transduction pathways. Through triggering downstream signaling pathways, FGFRs participate in various vital physiological processes, such as proliferation, differentiation, cell migration and survival.

Aberrant expression of FGFRs has been shown in various kinds of solid tumors, and moreover, the aberrancy is considered an oncogenic signaling pathway. It is believed that small molecules that competitively bind to the adenosine triphosphate (ATP) pocket of aberrant FGFRs while exhibiting little or no toxicity provide limitless prospects for the treatment of relevant tumors. The structure of FGFRs, especially the kinase domain, and the design of small molecular inhibitors have attracted intensive study in the past two decades. Multiple small molecule inhibitors have been developed, and some of them are currently being used in clinical trials, such as FGF401, which targets FGFR4 for the treatment of hepatocarcinoma (HCC); AZD4547, which targets FGFR1-3 for the treatment of a variety of tumors. Moreover, erdafitinib (JNJ-42756493) has been approved recently by U.S. Food and Drug Administration (FDA) for the treatment of mUC. More than 20 FGFR kinase/inhibitor complex structures have been determined to-date, and these structures have yielded extensive insights into the understanding of inactivation of FGFRs for related disease therapy.

2. Organization of FGFR

FGFRs share a canonical RTK architecture. From the N- to the C-terminus, all four FGFR members contain a large extracellular ligand-binding domain that comprises three immunoglobulin (Ig)-like subunits (D1, D2 and D3) followed by a single transmembrane helix and an intracellular tyrosine kinase domain (Figure 1A). The linker region between D1 and D2 contains a highly conserved motif that is rich in aspartate acids, called the acid box. The detailed function of those structural units will be further introduced below.

FGFs are the native ligand for this family of kinases. Through its extracellular domain, FGFR recognizes and is stimulated by specific FGFs. The FGF binding pocket is formed by the D2 and D3 subregions. There have been contradicting views regarding the stoichiometry of the FGF/FGFR complex. Schlessinger, J. et al. solved the ternary complex structure of FGF2/FGFR1/heparin. With the help of heparin, FGFR1 was dimerized after the binding of FGF2 to form the complex at a symmetric 2:2:2 stoichiometry ratio; both the FGF2 and heparin molecules simultaneously contacted the two FGFR1 monomers (Figure 1B). In the FGF1/FGFR2/heparin crystal structure solved by Pellegrini et al., the complex was assembled by asymmetric 2:2:1 stoichiometry. By utilizing nuclear magnetic resonance, Saxena et al. studied the interactions of FGF1(FGF2)/FGFR4/HM (HM: heparin mimetics) complex, and their results supported the formation of the symmetric mode of FGF/FGFR dimerization in solution. Interestingly, although all FGFs have a heparin sulfate binding site on their surface, endocrine FGFs such as FGF21 and FGF23 show a lower binding affinity to heparin sulfate and require Klotho coreceptors instead to act as cofactors for FGFR activation.

In addition to acting as the ligand sensor, the extracellular domain also undertakes an autoinhibitory role, which relies on regulation by D1 and the acid box. Several studies have proposed that the acid box could competitively bind to the heparin binding site of D2 to suppress heparin binding, while D1 forms intramolecular contacts with D2-D3, thus blocking the binding of FGFs. Nevertheless, the mechanisms of autoinhibition need to be further clarified.

3. Structure of FGFR Kinase Domain

The intracellular tyrosine kinase domain is the most well studied region of the FGFR protein. This domain exhibits the canonical bilobed architecture of protein kinases. The fold of the N-terminal small lobe (N-lobe, ~100 amino acid residues) consists of a five-stranded antiparallel β-sheet (β1–β5) and the αC-helix, an important regulatory element. The C-terminal large lobe (C-lobe, ~200 amino acid residues) predominately comprises seven a helices (αD, αE, αEF, αF-αI) (Figure 2A). The active site, which is responsible for ATP and substrate protein binding, is located in a clef between the two lobes (Figure 2B).

The C-lobe folds tightly with the αF-helix to form a hydrophobic core, around which the other secondary segments are packed. In addition to the primary helixes, the C-lobe contains a short helix located between the activation loop (A-loop) and the αF-helix named the αEF-helix, which is conserved among all FGFR members as well as other protein kinases. Two short β-strands (β7 and β8) (Figure 2A) between the catalytic loop and activation loop (introduced below) interact with each other and are believed to participate in the regulation of FGFR activation. In contrast to the C-lobe, the N-lobe folds in a more flexible manner, which benefits the binding and release of ATP/ADP and substrates.

There are several functionally important loops in both lobes. The loop between β8 and the αEF-helix is an activation loop (A-loop), which is essential for kinase activation. The conformation of the highly conserved Asp-Phe-Gly motif (DFG-motif) in the A-loop is an indicator of kinase activity status. Generally, the DFG-motif exists in two states: the active DFG-in and inactive DFG-out conformations (Figure 2C,D). In the DFG-in state, the aspartate residue of the DFG-motif plays an essential role in ATP binding through the coordination of all three phosphate groups of ATP, either directly or via magnesium ions, while these interactions are sterically impossible when the motif is flipped into the DFG-out conformation. Phosphorylation is catalyzed by the conserved aspartate of the His-Arg-Asp (HRD) motif in the catalytic (αE–β7) loop. The glycine rich P-loop (also called the nucleotide binding loop), located between the β1- and β2-strands, folds over to enclose ATP for phosphotransfer. The so-called molecular brake located at the hinge region that connects the N- and C-lobes plays a critical role in the regulation of autoinhibition and activation.

The catalytic activity of the kinase domain is precisely controlled. There are two general conformations for all protein kinases, including those of the FGFR family. Activation typically involves changes in the orientation of the αC-helix in the small lobe and the activation loop in the C-lobe. During the catalytic cycle, the active kinase toggles between open and closed conformations. In the open form, the kinase binds MgATP and the protein substrate, while during catalysis, the kinase adopts the closed form. Once catalysis is completed, the MgADP and phosphorylated substrate are released, and the enzyme recovers to the open conformation, preparing for the next catalytic cycle.

4. Characteristics of FGFR/Inhibitor Interaction

As noted above, aberrantly expressed FGFRs have been implicated in various tumors. Therefore, extensive work has been performed on the development of FGFR inhibitors. The inhibitors that are in clinical trials or approved by the FDA for clinical use are summarized in Table 1, and the chemical structures of those inhibitors are shown in Figure 3.

FGFR inhibitors can generally be divided into two groups according to their binding behaviors, namely, type I and type II inhibitors. Type I inhibitors bind FGFRs in the DFG-in enzymatic active conformation in an ATP-competitive manner, while the binding of type II requires the DFG-motif to be flipped to the DFG-out state. The X-ray crystallographic structures of AZD4547 (PDB ID 4V05) and PD173074 (PDB ID 2FGI) bound to FGFR1 demonstrate that these two inhibitors are type I inhibitors. Taking the FGFR1/AZD4547 structure as an example, the AZD4547 occupying the ATP pocket of FGFR1 forms a hydrogen bond with the backbone nitrogen atom of the DFG aspartate (Asp641) and forms three hydrogen bonds with the hinge residues (Figure 4A). In contrast, both the DFG-motifs of FGFR4 and FGFR1 are flipped out into an inactive conformation in the FGFR4/ponatinib (PDB ID 4UXQ) and FGFR1/ponatinib (PDB ID 4V04) structures. In addition to the basal interactions, a hydrogen bond formed between ponatinib and the side chain of the strictly conserved glutamate from the αC-helix (Glu520 in FGFR4 and Glu531 in FGFR1) was also observed, which is characteristic of a type II inhibitor (Figure 4B). Thus, these structures reveal ponatinib to be a type II inhibitor for FGFRs. As a consequence, the flip of the phenylalanine side chain breaks the regulatory spine and creates an additional induced-fit hydrophobic pocket that allows deeper binding of the inhibitor and provides better selectivity as well as slower dissociation kinetics.

The interaction between a small molecule inhibitor and protein kinase can be covalent (irreversible) or noncovalent (reversible). Typically, covalent inhibitors have a functional group known as the warhead, which can improve binding affinity and selectivity through covalent interaction with a certain residue of the target kinase. Moreover, a well-designed warhead could provide better performance against drug resistance than reversible inhibitors. The reported covalent reactive residues in protein kinases include cysteine, aspartic acid, lysine and others. For FGFRs, the conserved cysteine of the P-loop (C488 in FGFR1, C491 in FGFR2, C482 in FGFR3 and C477 in FGFR4) and the unique C552 in FGFR4 from the hinge region are the covalent binding sites. The FGFR4/FIIN-2 complex structure (PDB accession number 4QQC) is the first solved irreversible structure, where FIIN-2 formed a covalent bond through its reactive acrylamide group with the hydrosulfonyl side chain of FGFR4 C488 (Figure 4C).

5. Current Status of Small Molecule FGFR Inhibitor Development

Designing specific small molecule inhibitors targeting protein kinases is challenging because the ATP binding pockets of the human kinome are similar. Inhibitor research for FGFRs has gone through several stages. Initially, nonselective multiple-kinase inhibitors were developed to treat FGFR aberrations. Those nonselective inhibitors, including ponatinib, dovitinib lucitanib and nintedanib (see Table 1 for details), were originally designed for other kinases and then proved to have potent inhibition activity toward FGFRs. For instance, the type II inhibitor ponatinib was originally developed to overcome the BCR-ABL T315I gatekeeper mutant and showed single-digit nanomolar binding strength to FGFR1-4 in later researches. Although nonselective inhibitors might be clinically beneficial and achieve therapeutic success to some extent, the development of those inhibitors has been restricted due to the undesirable off-target toxicities.

To overcome the off-target effects of nonselective inhibitors, efforts have been made to develop FGFR-selective inhibitors (pan-FGFR inhibitors). In the earlier stage, multiple noncovalent pan-FGFR inhibitors were developed, including the well-known AZD4547 and LY2874455 (see Table 1 for details). Those pan-FGFR inhibitors are typically type I inhibitors. For example, AZD4547 is capable of potently inhibiting FGFR1-3 but shows negligible binding affinity to FGFR4. AZD4547 is currently in phase II clinical trials. However, preclinical data show that AZD4547 is not able to overcome the gatekeeper mutation V555M in FGFR3. Unlike AZD4547, the inhibitor LY2874455 shows inhibition efficacy against all 4 FGFRs, and the crystal structure as well as in vitro and vivo experiments confirmed that this inhibitor maintained equal inhibitory ability against the gatekeeper mutant V550M/V550L of FGFR4.

Given that covalent inhibitors confer better binding kinetics and selectivity than noncovalent ones, developing irreversible inhibitors of FGFRs has attracted intensive pharmaceutical and academic attention in recent years. Since the first covalent inhibitor FIIN-1, this field has achieved much progress. A number of FGFR covalent inhibitors have been developed, and some of those agents are already in clinical trials (see Table 1 for details). Moreover, several irreversible inhibitor/FGFR structures have been revealed by crystal structures, including FGFR4/BLU9931 (PDB ID: 4XCU), FGFR4/FIIN-3 (PDB ID: 4R6V), FGFR4/FIIN-2 (PDB ID: 4QQ5), FGFR4/CGA159527 (PDB ID: 5NUD), FGFR1(Y563C)/H3B-6527 (PDB ID: 5VND), and FGFR1/TAS-120 (PDB ID: 6MZW).

The kinase domains of FGFRs are highly homologous, with sequence identity varying from 74% to 77%. Unexpectedly, most of the reported pan-FGFR reversible inhibitors tend to bind FGFR1-3 but exhibit greatly reduced potency toward FGFR4. The underlying mechanism is not quite clear. Tucker et al. proposed that the innate flexibility of the FGFR4 kinase domain might be responsible for the decrease in binding ability. This feature, together with the unique C552 of FGFR4, which replaces a tyrosine in FGFR1-3, confers the opportunity to develop FGFR4-selective inhibitors (Figure 4D). Indeed, H3B-6527, BLU-9931, BLU-554 and FGF401 were developed as FGFR4-selective covalent inhibitors that target C552 for irreversible binding (Figure 4E). Among these four molecules, FGF401 is the most interesting because the covalent bond it forms is reversible, which reduces the off-target effect and prolongs the residence time. The crystal structure of FGF401/FGFR4 was recently reported by our laboratory (PDB ID 6JPJ), and its potential utility is currently under intensive research.

In addition to the kinase domain, the ectodomains of FGFRs have also attracted intensive interests for drug discovery. Unlike the highly conserved kinase domain, the ectodomains of FGFRs are less conserved; targeting this domain may offer better isoform selectivity. The dominant strategy to target FGFR ectodomains is using monoclonal antibody/antibody-drug conjugate. Several anti-FGFR monoclonal antibodies have been developed, and some of them are in clinical trials. In addition, efforts have been made in the development of small molecule inhibitor targeting FGFR ectodomains. An inhibitor, SSR128129E, which allosterically binds to the ectodomain of FGFR in a non-FGF competitive manner, has been reported to inhibit FGF-induced signaling.

6. FGFR Gatekeeper Mutation and Drug Resistance

The long-term efficacy of kinase inhibitors in cancer treatment is often disturbed by acquired resistance. One common mechanism of resistance is generated by mutating the so-called gatekeeper residue of the kinase domain. The gatekeeper mutation has been reported in various kinases, such as Bcr-Abl (T315I), EGFR (T790M), PDGFR (T674I), FGFR1 (V561M) and FGFR2 (V565I). The gatekeeper residue lies at the beginning of the hinge region and controls the accessibility of the hydrophobic pocket. Most protein kinases harbor a threonine that plays a major role in the interaction with the inhibitor by forming a critical hydrogen bond via its side chain hydroxyl oxygen. The mutation of this residue to a bulky hydrophobic amino acid, either Met or Ile, breaks the hydrogen interaction and introduces steric hindrance for inhibitor binding.

The drug resistance of FGFR gatekeeper mutations has been extensively verified, both in vitro and in vivo. For instance, the V564M mutation of FGFR2 confers the ability to resist dovitinib and BGJ398. Furthermore, an array of FGFR gatekeeper mutations have been identified in clinical samples. For example, the FGFR4 V550M mutation was detected in 13% of neuroendocrine breast carcinomas. In FGFRs, the gatekeeper residue is a valine (Figure 4D); as a consequence, its side chain cannot form hydrogen interactions with inhibitors (see above context), and the resistance thus arises mainly through the introduction of steric hindrance. Several FGFR inhibitors have been shown to have the ability to overcome FGFR gatekeeper mutations. For example, Ly2874455 has almost equal binding affinity to wild-type FGFR4, FGFR4 (V550M), FGFR4 (V550L) FGFR1 (V561M), FGFR2 (V564F) and FGFR3 (V555M); FGF401 has similar affinity to wild-type FGFR4, FGFR4 (V550M) and FGFR4 (V550L); FIIN-2 shows a binding affinity loss of ~10-fold for FGFR4 (V550L) compared with the wild-type kinase.

7. Conclusions

Increasing evidence indicates that aberrant Fibroblast growth factor receptors (FGFR)signaling plays a crucial role in tumorigenesis and progression. Now, small molecule inhibitors targeting FGFRs offer a novel and effective strategy for the therapy of cancers caused by FGFR aberrations. Efforts and progress have been made in the field of FGFR inhibitor development. Some small molecules show promising antitumor activity and are evaluated in clinical trials. Recently, the pan-FGFR inhibitor erdafitinib has been approved by the Food and Drug Administration for the treatment of mUC, making it the first approved FGFR-targeted drug. However, there are still challenges in the field of FGFR inhibitor development, such as the need for more potent and selective FGFR inhibitors, and inhibitors with the ability to overcome gatekeeper mutations. Most FGFR inhibitors currently under evaluation are typical type I inhibitors that occupy only the ATP binding pocket. Development of type II FGFR inhibitors, which could be inserted deeper into the pocket, could confer better potency and selectivity. In addition, the development of covalent irreversible or covalent reversible FGFR inhibitors might be another strategy to improve safety and efficacy for cancer treatment.

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    Vijayan R.S., He P., Modi V., Duong-Ly K.C., Ma H., Peterson J.R., Dunbrack R.L., Levy R.M. Conformational analysis of the DFG-out kinase motif and biochemical profiling of structurally validated type II inhibitors. J. Med. Chem. 2015;58:466-479.

    Not in our library10.1021/jm501603h

  44. 44.

    Klein T., Vajpai N., Phillips J.J., Davies G., Holdgate G.A., Phillips C., Tucker J.A., Norman R.A., Scott A.D., Higazi D.R., et al. Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase. Nat. Commun. 2015.

    Not in our library10.1038/ncomms8877

  45. 45.

    Guimaraes C.R., Rai B.K., Munchhof M.J., Liu S., Wang J., Bhattacharya S.K., Buckbinder L. Understanding the impact of the P-loop conformation on kinase selectivity. J. Chem. Inf. Model. 2011;51:1199-1204.

    Not in our library10.1021/ci200153c

  46. 46.

    Chen H., Ma J., Li W., Eliseenkova A.V., Xu C., Neubert T.A., Miller W.T., Mohammadi M. A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases. Mol. Cell. 2007;27:717-730.

    Not in our library10.1016/j.molcel.2007.06.028

  47. 47.

    Roskoski R. Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors. Pharm. Res. 2015;94:9-25.

    Not in our library10.1016/j.phrs.2015.01.003

  48. 48.

    Zhao G., Li W.Y., Chen D., Henry J.R., Li H.Y., Chen Z., Zia-Ebrahimi M., Bloem L., Zhai Y., Huss K., et al. A novel, selective inhibitor of fibroblast growth factor receptors that shows a potent broad spectrum of antitumor activity in several tumor xenograft models. Mol. Cancer. Ther. 2011;10:2200-2210.

    Not in our library10.1158/1535-7163.mct-11-0306

  49. 49.

    Nakanishi Y., Akiyama N., Tsukaguchi T., Fujii T., Sakata K., Sase H., Isobe T., Morikami K., Shindoh H., Mio T., et al. The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor. Mol. Cancer. Ther. 2014;13:2547-2558.

    Not in our library10.1158/1535-7163.mct-14-0248

  50. 50.

    Guagnano V., Furet P., Spanka C., Bordas V., Le Douget M., Stamm C., Brueggen J., Jensen M.R., Schnell C., Schmid H., et al. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamin o]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J. Med. Chem. 2011;54:7066-7083.

    Not in our library10.1021/jm2006222

  51. 51.

    Karkera J.D., Cardona G.M., Bell K., Gaffney D., Portale J.C., Santiago-Walker A., Moy C.H., King P., Sharp M., Bahleda R., et al. Oncogenic Characterization and Pharmacologic Sensitivity of Activating Fibroblast Growth Factor Receptor (FGFR) Genetic Alterations to the Selective FGFR Inhibitor Erdafitinib. Mol. Cancer. Ther. 2017;16:1717-1726.

    Not in our library10.1158/1535-7163.mct-16-0518

  52. 52.

    Collin M.P., Lobell M., Hubsch W., Brohm D., Schirok H., Jautelat R., Lustig K., Bomer U., Vohringer V., Heroult M., et al. Discovery of Rogaratinib (BAY 1163877): A pan-FGFR Inhibitor. Chem. Med. Chem. 2018;13:437-445.

    Not in our library10.1002/cmdc.201700718

  53. 53.

    Brameld K.A., Owens T.D., Verner E., Venetsanakos E., Bradshaw J.M., Phan V.T., Tam D., Leung K., Shu J., LaStant J., et al. Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(me thylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid Tumors. J. Med. Chem. 2017;60:6516-6527.

    Not in our library10.1021/acs.jmedchem.7b00360

  54. 54.

    Kalyukina M., Yosaatmadja Y., Middleditch M.J., Patterson A.V., Smaill J.B., Squire C.J. TAS-120 Cancer Target Binding: Defining Reactivity and Revealing the First Fibroblast Growth Factor Receptor 1 (FGFR1) Irreversible Structure. ChemMedChem. 2019;14:494-500.

    Not in our library10.1002/cmdc.201800719

  55. 55.

    Kim R., Sharma S., Meyer T., Sarker D., Macarulla T., Sung M., Choo S.P., Shi H., Schmidt-Kittler O., Clifford C., et al. First-in-human study of BLU-554, a potent, highly-selective FGFR4 inhibitor designed for hepatocellular carcinoma (HCC) with FGFR4 pathway activation. Eur. J. Cancer. 2016;69:S41.

    Not in our library10.1016/s0959-8049(16)32704-6

  56. 56.

    Joshi J.J., Coffey H., Corcoran E., Tsai J., Huang C.L., Ichikawa K., Prajapati S., Hao M.H., Bailey S., Wu J., et al. H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma. Cancer Res. 2017;77:6999-7013.

    Not in our library10.1158/0008-5472.can-17-1865

  57. 57.

    Zhou Z., Chen X., Fu Y., Zhang Y., Dai S., Li J., Chen L., Xu G., Chen Z., Chen Y. Characterization of FGF401 as a reversible covalent inhibitor of fibroblast growth factor receptor 4. Chem. Commun. (Camb.). 2019.

    Not in our library10.1039/c9cc02052g

  58. 58.

    Roskoski R. ERK1/2 MAP kinases: Structure, function, and regulation. Pharm. Res. 2012;66:105-143.

    Not in our library10.1016/j.phrs.2012.04.005

  59. 59.

    Dar A.C., Shokat K.M. The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Annu. Rev. Biochem. 2011;80:769-795.

    Not in our library10.1146/annurev-biochem-090308-173656

  60. 60.

    Norman R.A., Schott A.K., Andrews D.M., Breed J., Foote K.M., Garner A.P., Ogg D., Orme J.P., Pink J.H., Roberts K., et al. Protein-ligand crystal structures can guide the design of selective inhibitors of the FGFR tyrosine kinase. J. Med. Chem. 2012;55:5003-5012.

    Not in our library10.1021/jm3004043

  61. 61.

    Liu Y., Gray N.S. Rational design of inhibitors that bind to inactive kinase conformations. Nat. Chem. Biol. 2006;2:358-364.

    Not in our library10.1038/nchembio799

  62. 62.

    Mohammadi M., Froum S., Hamby J.M., Schroeder M.C., Panek R.L., Lu G.H., Eliseenkova A.V., Green D., Schlessinger J., Hubbard S.R. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J. 1998;17:5896-5904.

    Not in our library10.1093/emboj/17.20.5896

  63. 63.

    Davis M.I., Hunt J.P., Herrgard S., Ciceri P., Wodicka L.M., Pallares G., Hocker M., Treiber D.K., Zarrinkar P.P. Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol. 2011;29:1046-1051.

    Not in our library10.1038/nbt.1990

  64. 64.

    Baillie T.A. Targeted Covalent Inhibitors for Drug Design. Angew. Chem. Int. Ed. 2016;55:13408-13421.

    Not in our library10.1002/anie.201601091

  65. 65.

    Awoonor-Williams E., Walsh A.G., Rowley C.N. Modeling covalent-modifier drugs. Biochim. Biophys. Acta. 2017;1865:1664-1675.

    Not in our library10.1016/j.bbapap.2017.05.009

  66. 66.

    Liu Q., Sabnis Y., Zhao Z., Zhang T., Buhrlage S.J., Jones L.H., Gray N.S. Developing irreversible inhibitors of the protein kinase cysteinome. Chem. Biol. 2013;20:146-159.

    Not in our library10.1016/j.chembiol.2012.12.006

  67. 67.

    Serafimova I.M., Pufall M.A., Krishnan S., Duda K., Cohen M.S., Maglathlin R.L., McFarland J.M., Miller R.M., Frodin M., Taunton J. Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles. Nat. Chem. Biol. 2012;8:471-476.

    Not in our library10.1038/nchembio.925

  68. 68.

    Zhou W., Ercan D., Chen L., Yun C.H., Li D., Capelletti M., Cortot A.B., Chirieac L., Iacob R.E., Padera R., et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009;462:1070-1074.

    Not in our library10.1038/nature08622

  69. 69.

    Zhang J., Yang P.L., Gray N.S. Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer. 2009;9:28-39.

    Not in our library10.1038/nrc2559

  70. 70.

    Powis G., Bonjouklian R., Berggren M.M., Gallegos A., Abraham R., Ashendel C., Zalkow L., Matter W.F., Dodge J., Grindey G., et al. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res. 1994;54:2419-2423.

    Not in our library

  71. 71.

    Fox T., Fitzgibbon M.J., Fleming M.A., Hsiao H.M., Brummel C.L., Su M.S. Kinetic mechanism and ATP-binding site reactivity of p38gamma MAP kinase. FEBS Lett. 1999;461:323-328.

    Not in our library10.1016/s0014-5793(99)01488-x

  72. 72.

    Shannon D.A., Weerapana E. Covalent protein modification: The current landscape of residue-specific electrophiles. Curr. Opin. Chem. Biol. 2015;24:18-26.

    Not in our library10.1016/j.cbpa.2014.10.021

  73. 73.

    Tan L., Wang J., Tanizaki J., Huang Z., Aref A.R., Rusan M., Zhu S.J., Zhang Y., Ercan D., Liao R.G., et al. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors. Proc. Natl. Acad. Sci. USA. 2014;111:E4869-E4877.

    Not in our library10.1073/pnas.1403438111

  74. 74.

    Paul S.M., Mytelka D.S., Dunwiddie C.T., Persinger C.C., Munos B.H., Lindborg S.R., Schacht A.L. How to improve R&D productivity: The pharmaceutical industry’s grand challenge. Nat. Rev. Drug Discov. 2010;9:203-214.

    Not in our library10.1038/nrd3078

  75. 75.

    Fedorov O., Muller S., Knapp S. The (un)targeted cancer kinome. Nat. Chem. Biol. 2010;6:166-169.

    Not in our library10.1038/nchembio.297

  76. 76.

    O’Hare T., Shakespeare W.C., Zhu X., Eide C.A., Rivera V.M., Wang F., Adrian L.T., Zhou T., Huang W.S., Xu Q., et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401-412.

    Not in our library10.1016/j.ccr.2009.09.028

  77. 77.

    Trudel S., Li Z.H., Wei E., Wiesmann M., Chang H., Chen C., Reece D., Heise C., Stewart A.K. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005;105:2941-2948.

    Not in our library10.1182/blood-2004-10-3913

  78. 78.

    Bello E., Colella G., Scarlato V., Oliva P., Berndt A., Valbusa G., Serra S.C., D’Incalci M., Cavalletti E., Giavazzi R., et al. E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res. 2011;71:1396-1405.

    Not in our library10.1158/0008-5472.can-10-2700

  79. 79.

    Hilberg F., Roth G.J., Krssak M., Kautschitsch S., Sommergruber W., Tontsch-Grunt U., Garin-Chesa P., Bader G., Zoephel A., Quant J., et al. BIBF 1120: Triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68:4774-4782.

    Not in our library10.1158/0008-5472.can-07-6307

  80. 80.

    Nogova L., Sequist L.V., Perez Garcia J.M., Andre F., Delord J.P., Hidalgo M., Schellens J.H., Cassier P.A., Camidge D.R., Schuler M., et al. Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1–3 Kinase Inhibitor, in Patients with Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. J. Clin. Oncol. 2017;35:157-165.

    Not in our library10.1200/jco.2016.67.2048

  81. 81.

    Degirolamo C., Sabba C., Moschetta A. Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Nat. Rev. Drug Discov. 2016;15:51-69.

    Not in our library10.1038/nrd.2015.9

  82. 82.

    Chell V., Balmanno K., Little A.S., Wilson M., Andrews S., Blockley L., Hampson M., Gavine P.R., Cook S.J. Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance. Oncogene. 2013;32:3059-3070.

    Not in our library10.1038/onc.2012.319

  83. 83.

    Zhou W., Hur W., McDermott U., Dutt A., Xian W., Ficarro S.B., Zhang J., Sharma S.V., Brugge J., Meyerson M., et al. A structure-guided approach to creating covalent FGFR inhibitors. Chem. Biol. 2010;17:285-295.

    Not in our library10.1016/j.chembiol.2010.02.007

  84. 84.

    Hagel M., Miduturu C., Sheets M., Rubin N., Weng W., Stransky N., Bifulco N., Kim J.L., Hodous B., Brooijmans N., et al. First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway. Cancer Discov. 2015;5:424-437.

    Not in our library10.1158/2159-8290.cd-14-1029

  85. 85.

    Huang Z., Tan L., Wang H., Liu Y., Blais S., Deng J., Neubert T.A., Gray N.S., Li X., Mohammadi M. DFG-out mode of inhibition by an irreversible type-1 inhibitor capable of overcoming gate-keeper mutations in FGF receptors. ACS Chem. Biol. 2015;10:299-309.

    Not in our library10.1021/cb500674s

  86. 86.

    Fairhurst R.A., Knoepfel T., Leblanc C., Buschmann N., Gaul C., Blank J., Galuba I., Trappe J., Zou C., Voshol J., et al. Approaches to selective fibroblast growth factor receptor 4 inhibition through targeting the ATP-pocket middle-hinge region. MedChemComm. 2017;8:1604-1613.

    Not in our library10.1039/c7md00213k

  87. 87.

    Ho H.K., Yeo A.H., Kang T.S., Chua B.T. Current strategies for inhibiting FGFR activities in clinical applications: Opportunities, challenges and toxicological considerations. Drug Discov. Today. 2014;19:51-62.

    Not in our library10.1016/j.drudis.2013.07.021

  88. 88.

    Katoh M. FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review). Int. J. Mol. Med. 2016;38:3-15.

    Not in our library10.3892/ijmm.2016.2620

  89. 89.

    Lu X., Chen H., Patterson A.V., Smaill J.B., Ding K. Fibroblast Growth Factor Receptor 4 (FGFR4) Selective Inhibitors as Hepatocellular Carcinoma Therapy: Advances and Prospects. J. Med. Chem. 2019;62:2905-2915.

    Not in our library10.1021/acs.jmedchem.8b01531

  90. 90.

    Hierro C., Rodon J., Tabernero J. Fibroblast Growth Factor (FGF) Receptor/FGF Inhibitors: Novel Targets and Strategies for Optimization of Response of Solid Tumors. Semin. Oncol. 2015;42:801-819.

    Not in our library10.1053/j.seminoncol.2015.09.027

  91. 91.

    Bradshaw J.M., McFarland J.M., Paavilainen V.O., Bisconte A., Tam D., Phan V.T., Romanov S., Finkle D., Shu J., Patel V., et al. Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat. Chem. Biol. 2015;11:525-531.

    Not in our library10.1038/nchembio.1817

  92. 92.

    Knoepfel T., Furet P., Mah R., Buschmann N., Leblanc C., Ripoche S., Graus-Porta D., Wartmann M., Galuba I., Fairhurst R.A. 2-Formylpyridyl Ureas as Highly Selective Reversible-Covalent Inhibitors of Fibroblast Growth Factor Receptor 4. ACS Med. Chem. Lett. 2018;9:215-220.

    Not in our library10.1021/acsmedchemlett.7b00485

  93. 93.

    Shabani M., Hojjat-Farsangi M. Targeting Receptor Tyrosine Kinases Using Monoclonal Antibodies: The Most Specific Tools for Targeted-Based Cancer Therapy. Curr. Drug Targets. 2016;17:1687-1703.

    Not in our library10.2174/1389450116666151001104133

  94. 94.

    Pierce K.L., Deshpande A.M., Stohr B.A., Gemo A.T., Patil N.S., Brennan T.J., Bellovin D.I., Palencia S., Giese T., Huang C., et al. FPA144, a humanized monoclonal antibody for both FGFR2-amplified and nonamplified, FGFR2b-overexpressing gastric cancer patients. J. Clin. Oncol. 2014.

    Not in our library10.1200/jco.2014.32.15_suppl.e15074

  95. 95.

    Sommer A., Kopitz C., Schatz C.A., Nising C.F., Mahlert C., Lerchen H.G., Stelte-Ludwig B., Hammer S., Greven S., Schuhmacher J., et al. Preclinical Efficacy of the Auristatin-Based Antibody-Drug Conjugate BAY 1187982 for the Treatment of FGFR2-Positive Solid Tumors. Cancer Res. 2016;76:6331-6339.

    Not in our library10.1158/0008-5472.can-16-0180

  96. 96.

    Schatz C.A., Kopitz C., Wittemer-Rump S., Sommer A., Lindbom L., Osada M., Yamanouchi H., Huynh H., Krahn T., Asadullah K. Abstract 4766: Pharmacodynamic and stratification biomarker for the anti-FGFR2 antibody (BAY1179470) and the FGFR2-ADC. Cancer Res. 2014.

    Not in our library10.1158/1538-7445.am2014-4766

  97. 97.

    Trudel S., Bergsagel P.L., Singhal S., Niesvizky R., Comenzo R.L., Bensinger W.I., Lebovic D., Choi Y., Lu D., French D., et al. A Phase I Study of the Safety and Pharmacokinetics of Escalating Doses of MFGR1877S, a Fibroblast Growth Factor Receptor 3 (FGFR3) Antibody, in Patients with Relapsed or Refractory t(4;14)-Positive Multiple Myeloma. Blood. 2012;120:4029.

    Not in our library

  98. 98.

    Blackwell C., Sherk C., Fricko M., Ganji G., Barnette M., Hoang B., Tunstead J., Skedzielewski T., Alsaid H., Jucker B.M., et al. Inhibition of FGF/FGFR autocrine signaling in mesothelioma with the FGF ligand trap, FP-1039/GSK3052230. Oncotarget. 2016;7:39861-39871.

    Not in our library10.18632/oncotarget.9515

  99. 99.

    Bono F., De Smet F., Herbert C., De Bock K., Georgiadou M., Fons P., Tjwa M., Alcouffe C., Ny A., Bianciotto M., et al. Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. Cancer Cell. 2013;23:477-488.

    Not in our library10.1016/j.ccr.2013.02.019

  100. 100.

    Herbert C., Schieborr U., Saxena K., Juraszek J., De Smet F., Alcouffe C., Bianciotto M., Saladino G., Sibrac D., Kudlinzki D., et al. Molecular mechanism of SSR128129E, an extracellularly acting, small-molecule, allosteric inhibitor of FGF receptor signaling. Cancer Cell. 2013;23:489-501.

    Not in our library10.1016/j.ccr.2013.02.018

  101. 101.

    Babina I.S., Turner N.C. Advances and challenges in targeting FGFR signalling in cancer. Nat. Rev. Cancer. 2017;17:318-332.

    Not in our library10.1038/nrc.2017.8

  102. 102.

    Cheetham G.M., Charlton P.A., Golec J.M., Pollard J.R. Structural basis for potent inhibition of the Aurora kinases and a T315I multi-drug resistant mutant form of Abl kinase by VX-680. Cancer Lett. 2007;251:323-329.

    Not in our library10.1016/j.canlet.2006.12.004

  103. 103.

    Weisberg E., Choi H.G., Ray A., Barrett R., Zhang J., Sim T., Zhou W., Seeliger M., Cameron M., Azam M., et al. Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: Novel type II inhibitor of gatekeeper mutants. Blood. 2010;115:4206-4216.

    Not in our library10.1182/blood-2009-11-251751

  104. 104.

    Ryan M.R., Sohl C.D., Luo B., Anderson K.S. The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT. Mol. Cancer Res. 2019;17:532-543.

    Not in our library10.1158/1541-7786.mcr-18-0429

  105. 105.
    The N550K/H Mutations in FGFR2 Confer Differential Resistance to PD173074, Dovitinib, and Ponatinib ATP-Competitive Inhibitors · 2013
    Not checked
  106. 106.

    Yoza K., Himeno R., Amano S., Kobashigawa Y., Amemiya S., Fukuda N., Kumeta H., Morioka H., Inagaki F. Biophysical characterization of drug-resistant mutants of fibroblast growth factor receptor 1. Genes Cells. 2016;21:1049-1058.

    Not in our library10.1111/gtc.12405

  107. 107.

    Goyal L., Saha S.K., Liu L.Y., Siravegna G., Leshchiner I., Ahronian L.G., Lennerz J.K., Vu P., Deshpande V., Kambadakone A., et al. Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma. Cancer Discov. 2017;7:252-263.

    Not in our library10.1158/2159-8290.cd-16-1000

  108. 108.

    Ang D., Ballard M., Beadling C., Warrick A., Schilling A., O’Gara R., Pukay M., Neff T.L., West R.B., Corless C.L., et al. Novel mutations in neuroendocrine carcinoma of the breast: Possible therapeutic targets. Appl. Immunohistochem. Mol. Morphol. 2015;23:97-103.

    Not in our library10.1097/pdm.0b013e3182a40fd1

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