Characterization of the cholangiocarcinoma drug pemigatinib against FGFR gatekeeper mutants

Lin, Qianmeng; Chen, Xiaojuan; Qu, Lingzhi; Guo, Ming; Wei, Hudie; Dai, Shuyan; Jiang, Longying; Chen, Yongheng

doi:10.1038/s42004-022-00718-z

Cited by 18 publications

(14 citation statements)

References 53 publications

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“…This mutation was identified in several FGFR2 fusion-positive cholangiocarcinoma patients who progressed after treatment with infigratinib ( 52 ). All three inhibitors bind the inactive conformation of FGFR ( 53 , 54 ), which might explain their relatively modest potency on the AN3-CA cell line compared to the other FGFR -altered cell lines.…”

Section: Resultsmentioning

confidence: 99%

Comparative kinase and cancer cell panel profiling of kinase inhibitors approved for clinical use from 2018 to 2020

Kooijman¹,

Riel²,

Dylus³

et al. 2022

Front. Oncol.

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During the last two decades, kinase inhibitors have become the major drug class for targeted cancer therapy. Although the number of approved kinase inhibitors increases rapidly, comprehensive in vitro profiling and comparison of inhibitor activities is often lacking in the public domain. Here we report the extensive profiling and comparison of 21 kinase inhibitors approved by the FDA for oncology indications since June 2018 and 13 previously approved comparators on panels of 255 biochemical kinase assays and 134 cancer cell line viability assays. Comparison of the cellular inhibition profiles of the EGFR inhibitors gefitinib, dacomitinib, and osimertinib identified the uncommon EGFR p.G719S mutation as a common response marker for EGFR inhibitors. Additionally, the FGFR inhibitors erdafitinib, infigratinib, and pemigatinib potently inhibited the viability of cell lines which harbored oncogenic alterations in FGFR1-3, irrespective of the specific clinical indications of the FGFR inhibitors. These results underscore the utility of in vitro kinase inhibitor profiling in cells for identifying new potential stratification markers for patient selection. Furthermore, comparison of the in vitro inhibition profiles of the RET inhibitors pralsetinib and selpercatinib revealed they had very similar biochemical and cellular selectivity. As an exception, an NTRK3 fusion-positive cell line was potently inhibited by pralsetinib but not by selpercatinib, which could be explained by the targeting of TRK kinases in biochemical assays by pralsetinib but not selpercatinib. This illustrates that unexpected differences in cellular activities between inhibitors that act through the same primary target can be explained by subtle differences in biochemical targeting. Lastly, FLT3-mutant cell lines were responsive to both FLT3 inhibitors gilteritinib and midostaurin, and the PI3K inhibitor duvelisib. Biochemical profiling revealed that the FLT3 and PI3K inhibitors targeted distinct kinases, indicating that unique dependencies can be identified by combined biochemical and cellular profiling of kinase inhibitors. This study provides the first large scale kinase assay or cell panel profiling study for newly approved kinase inhibitors, and shows that comprehensive in vitro profiling of kinase inhibitors can provide rationales for therapy selection and indication expansion of approved kinase inhibitors.

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Section: Resultsmentioning

confidence: 99%

Comparative kinase and cancer cell panel profiling of kinase inhibitors approved for clinical use from 2018 to 2020

Kooijman¹,

Riel²,

Dylus³

et al. 2022

Front. Oncol.

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“…Introducing bulky isoleucine, methionine, and phenylalanine residues at the gatekeeper position of FGFR leads to severe steric clash with the indole group of sulfatinib. Consequently, the clash disrupts the hydrogen binding with Ala564 of the hinge region and Glu531 surrounding the hydrophobic pocket [32][33][34] . The flexible oxy linker may assist in shifting the indole group out of this pocket, resulting in a CSF-1R/sulfatinib-like binding model to better accommodate gatekeeper mutation and maintain hydrogen contacts with the hinge residue.…”

Section: Discussionmentioning

confidence: 99%

“…Expression and purification of the human FGFR kinase domain. FGFRs were prepared as previously described 6,34,44,45 . Briefly, FGFR1 (residues 458-765), FGFR2 (residues 458-768), FGFR3 (residues 450-758) as well as FGFR4 (residues 445-753), and their mutants, FGFR1 C584S , FGFR1 V561M , FGFR2 V564I , FGFR2 V564F and FGFR3 V555M , were cloned into a modified pET28a vector in frame with an N-terminal PreScission-cleavable 6×His tag and expressed in E. coli BL21 Rosetta cells.…”

Section: Methodsmentioning

confidence: 99%

Structural basis and selectivity of sulfatinib binding to FGFR and CSF-1R

Lin,

Dai,

et al. 2024

Commun Chem

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Acquired drug resistance poses a challenge for single-target FGFR inhibitors, leading to the development of dual- or multi-target FGFR inhibitors. Sulfatinib is a multi-target kinase inhibitor for treating neuroendocrine tumors, selectively targeting FGFR1/CSF-1R. To elucidate the molecular mechanisms behind its binding and kinase selectivity, we determined the crystal structures of sulfatinib with FGFR1/CSF-1R. The results reveal common structural features and distinct conformational adaptability of sulfatinib in response to FGFR1/CSF-1R binding. Further biochemical and structural analyses disclose sensitivity of sulfatinib to FGFR/CSF-1R gatekeeper mutations. The insensitivity of sulfatinib to FGFR gatekeeper mutations highlights the indispensable interactions with the hydrophobic pocket for FGFR selectivity, whereas the rotatory flexibility may enable sulfatinib to overcome CSF-1RT663I. This study not only sheds light on the structural basis governing sulfatinib’s FGFR/CSF-1R inhibition, but also provides valuable insights into the rational design of dual- or multi-target FGFR inhibitors with selectivity for CSF-1R and sensitivity to gatekeeper mutations.

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“…The crystal structure of FGFR1 complexed with pemigatinib (PDB ID 7WCL) was downloaded from the Protein Data Bank (PDB). The protonation state of all ionizable amino acids was determined at pH 7.4 using PROPKA 3.1 .…”

Section: Methodsmentioning

confidence: 99%

Discovery of Novel Naphthoquinone–Chalcone Hybrids as Potent FGFR1 Tyrosine Kinase Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling

Leechaisit,

Mahalapbutr,

Boonsri

et al. 2023

ACS Omega

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This work presents a flexible synthesis of 10 novel naphthoquinone–chalcone derivatives ( 1 – 10 ) by nucleophilic substitution of readily accessible aminochalcones and 2,3-dichloro-1,4-naphthoquinone. All compounds displayed broad-spectrum cytotoxic activities against all the tested cancer cell lines (i.e., HuCCA-1, HepG2, A549, MOLT-3, T47D, and MDA-MB-231) with IC 50 values in the range of 0.81–62.06 μM, especially the four most potent compounds 1 , 3 , 8 , and 9 . The in vitro investigation on the fibroblast growth factor receptor 1 (FGFR1) inhibitory effect indicated that eight derivatives ( 1 – 2 , 4 – 5 , and 7 – 10 ) were active FGFR1 inhibitors (IC 50 = 0.33–3.13 nM) with more potency than that of the known FGFR1 inhibitor, AZD4547 (IC 50 = 12.17 nM). Promisingly, compounds 5 (IC 50 = 0.33 ± 0.01 nM), 9 (IC 50 = 0.50 ± 0.04 nM), and 7 (IC 50 = 0.85 ± 0.08 nM) were the three most potent FGFR1 inhibitors. Molecular docking, molecular dynamics simulations, and MM/GBSA-based free energy calculation revealed that the key amino acid residues involved in the binding of the compounds 5 , 7 , and 9 and the target FGFR1 protein were similar with those of the AZD4547 (i.e., Val492, Lys514, Ile545, Val561, Ala640, and Asp641). These findings revealed that the newly synthesized naphthoquinone–chalcone scaffold is a promising structural feature for an efficient inhibition of FGFR1.

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Characterization of the cholangiocarcinoma drug pemigatinib against FGFR gatekeeper mutants

Cited by 18 publications

References 53 publications

Comparative kinase and cancer cell panel profiling of kinase inhibitors approved for clinical use from 2018 to 2020

Comparative kinase and cancer cell panel profiling of kinase inhibitors approved for clinical use from 2018 to 2020

Structural basis and selectivity of sulfatinib binding to FGFR and CSF-1R

Discovery of Novel Naphthoquinone–Chalcone Hybrids as Potent FGFR1 Tyrosine Kinase Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling

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