Structural insights into the potency and selectivity of covalent pan-FGFR inhibitors

Qu, Lingzhi; Chen, Xiaojuan; Wei, Hudie; Guo, Ming; Dai, Shuyan; Jiang, Longying; Li, Jun; Yue, Sitong; Chen, Zhuchu; Chen, Yongheng

doi:10.1038/s42004-021-00623-x

Cited by 15 publications

(13 citation statements)

References 41 publications

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“…Pemigatinib was redocked into FGFR1 to evaluate the reliability of this method. Then, pemigatinib was docked into FGFR2 (PDB ID: 6LVL) 28 , FGFR3 (PDB ID:7DHL) 29 and FGFR4 (PDB ID: 7F3M) 30 , respectively. Structural models predict that FGFR1-4 in complex with pemigatinib exhibit similar binding modes and similar interaction patterns (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Characterization of the cholangiocarcinoma drug pemigatinib against FGFR gatekeeper mutants

Lin

Chen

et al. 2022

Commun Chem

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Fibroblast growth factor receptor (FGFR) dysregulation is involved in a variety of tumorigenesis and development. Cholangiocarcinoma is closely related with FGFR aberrations, and pemigatinib is the first drug approved to target FGFR for the treatment of cholangiocarcinoma. Herein, we undertake biochemical and structural analysis on pemigatinib against FGFRs as well as gatekeeper mutations. The results show that pemigatinib is a potent and selective FGFR1–3 inhibitor. The extensive network of hydrogen bonds and van der Waals contacts found in the FGFR1-pemigatinib binding mode accounts for the high potency. Pemigatinib also has excellent potency against the Val-to-Ile gatekeeper mutation but less potency against the Val-to-Met/Phe gatekeeper mutation in FGFR. Taken together, the inhibitory and structural profiles exemplified by pemigatinib may help to thwart Val-to-Ile gatekeeper mutation-based resistance at earlier administration and to advance the further design and improvement for inhibitors toward FGFRs with gatekeeper mutations.

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Section: Resultsmentioning

confidence: 99%

Characterization of the cholangiocarcinoma drug pemigatinib against FGFR gatekeeper mutants

Lin

Chen

et al. 2022

Commun Chem

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“…All FGFR4 constructs were prepared as previously described. ,,− Briefly, the FGFR4 kinase domain (residues 445–753) was cloned into a modified pET28a vector with an N-terminal PreScission protease-cleavable 6xHis tag. The FGFR4 kinase domain (residues 442–802) with an N-terminal TEL (residues 1–183) was cloned into pMSCVpuro (Clontech).…”

Section: Methodsmentioning

confidence: 99%

“…All FGFR4 crystals were grown at 4 °C by hanging drop vapor diffusion with well solution (15–21% PEG-3350, 0.1 M Bis–Tris, pH 4.5, and 0.2 M Li 2 SO 4 ), then quickly transferred to mother liquor supplemented with 20% glycerol and flash-frozen in liquid nitrogen. FGFR4/ 8k , FGFR4/ 8z , FGFR4 V550L / 8z , and FGFR4 V550M / 8z crystal data sets were collected at the BL19U136 beamlines of Shanghai Synchrotron Radiation Facility (SSRF), while the FGFR4/ 8r crystal data set was collected using an in-house MicroMax-007 X-ray generator equipped with VariMax HR optics (Rigaku, Japan) and processed using the HKL3000. , All structures were solved by molecular replacement using PHENIX Phaser with FGFR4/ 10z (PDB ID: 7YBO) as the search model for FGFR4/ 8r and FGFR4/ 8z , FGFR4 V550L / 7v (PDB ID: 7WCW) for FGFR4 V550L / 8z , and FGFR4 V550M / 7v (PDB ID: 7WCX) for FGFR4 V550M / 8z . The ligands were modeled in PRODRG Web site and fitted by Phenix.…”

Section: Methodsmentioning

confidence: 99%

Discovery of 6-Formylpyridyl Urea Derivatives as Potent Reversible-Covalent Fibroblast Growth Factor Receptor 4 Inhibitors with Improved Anti-Hepatocellular Carcinoma Activity

Yang,

Lin,

Song

et al. 2024

J. Med. Chem.

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Fibroblast growth factor receptor 4 (FGFR4) has been considered as a potential anticancer target due to FGF19/ FGFR4 mediated aberrant signaling in hepatocellular carcinoma (HCC). Several FGFR4 inhibitors have been reported, but none have gained approval. Herein, a series of 5-formyl-pyrrolo[3,2-b]pyridine-3-carboxamides and a series of 6-formylpyridyl ureas were characterized as selective reversible-covalent FGFR4 inhibitors. The representative 6-formylpyridyl urea 8z exhibited excellent potency against FGFR4 WT , FGFR4 V550L , and FGFR4 V550M with IC 50 values of 16.3, 12.6, and 57.3 nM, respectively. It also potently suppressed proliferation of Ba/F3 cells driven by FGFR4 WT , FGFR4 V550L , and FGFR4 V550M , and FGFR4-dependent Hep3B and Huh7 HCC cells, with IC 50 values of 1.2, 13.5, 64.5, 15.0, and 20.4 nM, respectively. Furthermore, 8z displayed desirable microsomal stability and significant in vivo efficacy in the Huh7 HCC cancer xenograft model in nude mice. The study provides a promising new lead for anticancer drug discovery directed toward overcoming FGFR4 gatekeeper mutation mediated resistance in HCC patients.

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“…All constructs were prepared as previously described. ,, Briefly, the FGFR4 kinase domain, containing an N-terminal 6xHis tag followed by a PreScission cleavage site, was cloned into pET28a vector. The N -terminal of TEL followed by FGFR4 kinase domain (TEL-FGFR4) constructs were cloned into pMSCVpuro (Clontech).…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 5-Formyl-pyrrolo[3,2-b]pyridine-3-carboxamides as New Selective, Potent, and Reversible-Covalent FGFR4 Inhibitors

et al. 2022

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The FGF19-FGFR4 signaling pathway has been extensively studied as a promising target for the treatment of hepatocellular carcinoma (HCC). Several FGFR4-selective inhibitors have been developed, but none of them receives approval. Additionally, acquired resistance caused by FGFR4 gatekeeper mutations is emerging as a serious limitation for these targeted therapies. Herein, we report a novel series of 5-formyl-pyrrolo[3,2-b]pyridine derivatives as new reversible-covalent inhibitors targeting wild-type and gatekeeper mutant variants of FGFR4 kinase. The representative compound 10z exhibited single-digit nanomolar activity against wild-type FGFR4 and the FGFR4V550L/M mutant variants in biochemical and Ba/F3 cellular assays, while sparing FGFR1/2/3. Furthermore, 10z showed significant antiproliferative activity against Hep3B, JHH-7, and HuH-7 HCC cells with IC50 values of 37, 32, and 94 nM, respectively. MALDI-TOF-MS and X-ray protein crystallography studies were consistent with 10z acting as a reversible-covalent inhibitor of FGFR4, serving as a promising lead compound for further anticancer drug development.

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Structural insights into the potency and selectivity of covalent pan-FGFR inhibitors

Cited by 15 publications

References 41 publications

Characterization of the cholangiocarcinoma drug pemigatinib against FGFR gatekeeper mutants

Characterization of the cholangiocarcinoma drug pemigatinib against FGFR gatekeeper mutants

Discovery of 6-Formylpyridyl Urea Derivatives as Potent Reversible-Covalent Fibroblast Growth Factor Receptor 4 Inhibitors with Improved Anti-Hepatocellular Carcinoma Activity

Design, Synthesis, and Biological Evaluation of 5-Formyl-pyrrolo[3,2-b]pyridine-3-carboxamides as New Selective, Potent, and Reversible-Covalent FGFR4 Inhibitors

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