The 1.65 Å resolution structure of the complex of AZD4547 with the kinase domain of FGFR1 displays exquisite molecular recognition

Yosaatmadja, Y.; Patterson, Adam V.; Smaill, Jeff B.; Squire, C.J.

doi:10.1107/s1399004714027539

Cited by 27 publications

(13 citation statements)

References 47 publications

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“…Recombinant protein production : Recombinant protein production was carried out as described previously . In brief, DNA encoding the FGFR1 kinase domain harbouring C488A/C584S or C584S mutations were cloned into the pETDuet vector (Merck) along with the complete gene for human PTP1B phosphatase.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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1‐[(3S)‐3‐[4‐Amino‐3‐[2‐(3,5‐dimethoxyphenyl)ethynyl]‐1H‐pyrazolo[3,4‐d]pyrimidin‐1‐yl]‐1‐pyrrolidinyl]‐2‐propen‐1‐one (TAS‐120) is an irreversible inhibitor of the fibroblast growth factor receptor (FGFR) family, and is currently under phase I/II clinical trials in patients with confirmed advanced metastatic solid tumours harbouring FGFR aberrations. This inhibitor specifically targets the P‐loop of the FGFR tyrosine kinase domain, forming a covalent adduct with a cysteine side chain of the protein. Our mass spectrometry experiments characterise an exceptionally fast chemical reaction in forming the covalent complex. The structural basis of this reactivity is revealed by a sequence of three X‐ray crystal structures: a free ligand structure, a reversible FGFR1 structure, and the first reported irreversible FGFR1 adduct structure. We hypothesise that the most significant reactivity feature of TAS‐120 is its inherent ability to undertake conformational sampling of the FGFR P‐loop. In designing novel covalent FGFR inhibitors, such a phenomenon presents an attractive strategy requiring appropriate positioning of an acrylamide group similarly to that of TAS‐120.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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“…Most selective FGFR1 inhibitors are ATP-competitive inhibitors that bind to the ATP-binding pocket of FGFR. The ATP binding pocket of the FGFR1 consists of five regions 3 ,23,24 : (i) the adenine region, (ii) hydrophobic region I, (iii) hydrophobic region II, (iv) the nucleotide domain, (v) and the phosphate region. The adenine region is considered as the major binding site in which heterocycle scaffolds are anchored through several H-bonds with a hinge region of the kinase (Figure 1, red colour).…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening

Liu

Wen

Gao

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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2020) Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening, Journal of Enzyme Inhibition and Medicinal Chemistry, 35:1, 72-84, ABSTRACTFibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragmentbased virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC 50 ¼ 15.0 nM) and modest anti-proliferative activity (IC 50 ¼ 785.8 nM). Through two rounds of optimisation, the indazole derivative 9 u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC 50 ¼ 3.3 nM) and cellular activity (IC 50 ¼ 468.2 nM). Moreover, 9 u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1. GRAPHICAL ABSTRACT ARTICLE HISTORY

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“…AZD4547 is a potent and selective small-molecule inhibitor of FGFR1 with an IC 50 value of 0.2 nM and currently in phase II and III clinical trials for the treatment of cancer (ClinicalTrials.gov Identifier: NCT02154490). The 1.65 A° resolution crystal structure of AZD4547 bound to the kinase domain of FGFR1 has been determined and reveals AZD4547 to be a type 1 kinase inhibitor targeting the active kinase conformation of FGFR1 [ 52 ]. In the present study, a significant decline of ~40% in the pulmonary rickettsial load in AZD4547-treated, R .…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor receptor-1 mediates internalization of pathogenic spotted fever rickettsiae into host endothelium

et al. 2017

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Rickettsial infections continue to cause serious morbidity and mortality in severe human cases around the world. Host cell adhesion and invasion is an essential requisite for intracellular growth, replication, and subsequent dissemination of pathogenic rickettsiae. Heparan sulfate proteoglycans [HSPGs] facilitate the interactions between fibroblast growth factor(s) and their tyrosine kinase receptors resulting in receptor dimerization/activation and have been implicated in bacterial adhesion to target host cells. In the present study, we have investigated the contributions of fibroblast growth factor receptors [FGFRs] in rickettsial entry into the host cells. Inhibition of HSPGs by heparinase and FGFRs by AZD4547 (a selective small-molecule inhibitor) results in significant reduction in rickettsial internalization into cultured human microvascular endothelial cells (ECs), which represent the primary targets of pathogenic rickettsiae during human infections. Administration of AZD4547 during R. conorii infection in a murine model of endothelial-target spotted fever rickettsiosis also diminishes pulmonary rickettsial burden in comparison to mock-treated controls. Silencing of FGFR1 expression using a small interfering RNA also leads to similar inhibition of R. rickettsii invasion into ECs. Consistent with these findings, R. rickettsii infection of ECs also results in phosphorylation of tyrosine 653/654, suggesting activation of FGFR1. Using isobaric tag for relative and absolute quantitation [iTRAQ]-based proteomics approach, we further demonstrate association of β-peptide of rickettsial outer membrane protein OmpA with FGFR1. Mechanistically, FGFR1 binds to caveolin-1 and mediates bacterial entry via caveolin-1 dependent endocytosis. Together, these results identify host cell FGFR1 and rickettsial OmpA as another novel receptor-ligand pair contributing to the internalization of pathogenic rickettsiae into host endothelial cells and the potential application of FGFR-inhibitor drugs as adjunct therapeutics against spotted fever rickettsioses.

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The 1.65 Å resolution structure of the complex of AZD4547 with the kinase domain of FGFR1 displays exquisite molecular recognition

Cited by 27 publications

References 47 publications

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

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

Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening

Fibroblast growth factor receptor-1 mediates internalization of pathogenic spotted fever rickettsiae into host endothelium

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