Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4

Fairhurst, Robin A.; Knoepfel, Thomas; Buschmann, Nicole; Leblanc, Catherine; Mah, Robert; Todorov, Milen; Nimsgern, Pierre; Ripoche, Sebastien; Niklaus, Michel; Warin, Nicolas; Luu, Van Huy; Madoerin, Mario; Wirth, Jasmin; Graus‐Porta, Diana; Weiss, Andreas; Kiffe, Michael; Wartmann, Markus; Kinyamu-Akunda, Jacqueline; Sterker, Dario; Stamm, Christelle; Adler, Flavia; Buhles, Alexandra; Schadt, Heiko S.; Couttet, Philippe; Blank, Jutta; Galuba, Inga; Trappe, Joerg; Voshol, Johannes; Ostermann, Nils; Zou, Chao; Berghausen, Joerg; Espinola, Alberto Del Rio; Jahnke, Wolfgang; Furet, Pascal

doi:10.1021/acs.jmedchem.0c01019

Cited by 79 publications

(94 citation statements)

References 78 publications

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“…Our result is supported by a recent study that demonstrated significant benefits of EP300/CBP inhibitors in AR--positive BRCA and AR-positive PRAD cell lines with negligible effects on IC50’s for AR--negative cancers 66 . We also identified FGFR4 in LIHC with recent studies showing strong evidence to suggest the efficacy of an inhibitor, Roblitinib, in vitro and in vivo with xenograft models providing strong support to our results 67 . We find other chromatin modulators such as BRD7 in low grade glioma (LGG), BRD9 in Liver/Hepatocellular carcinoma (LIHC) and KDM5A in TGCT, KDM1A, KDM4A, KMT5B and KDM5C in PRAD as high priority druggable genes.…”

Section: Resultssupporting

confidence: 87%

Discovery of novel therapeutic targets in cancer using patient-specific gene regulatory networks

Forbes

Cohen

et al. 2022

Preprint

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Most cancer types lack effective targeted therapeutic options and in cancers where first-line targeted therapies are available, treatment resistance is a huge challenge. Recent technological advances enable the use of ATAC-seq and RNA-seq on patient biopsies in a high-throughput manner. Here we present a computational approach that leverages these datasets to identify novel drug targets based on tumor lineage. We constructed patient-specific gene regulatory networks for 371 patients of 22 cancer types using machine learning approaches trained using three-dimensional genomic data for enhancer to promoter contacts. Next, we identify the key transcription factors (TFs) in these networks, which are used to identify therapeutic vulnerabilities either by direct targeting of TFs or proteins that they co-operate with. We validate four novel candidates identified for neuroendocrine, liver and renal cancers, which have a dismal prognosis with current therapeutic options. We present a novel approach to use the increasing amounts of functional genomics data from patient biospecimens for identification of novel drug targets.

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Section: Resultssupporting

confidence: 87%

Discovery of novel therapeutic targets in cancer using patient-specific gene regulatory networks

Forbes

Cohen

et al. 2022

Preprint

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“…THNs feature prominently as arginine mimics in αv integrin inhibitors (e.g., 23 ), 47 and the THN scaffold has also been deployed as a semi-saturated bioisostere of a quinoline, to enhance compound solubility (e.g., 24 ). 48 …”

Section: Resultsmentioning

confidence: 99%

Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines

et al. 2021

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Catalytic, intermolecular hydroaminoalkylation (HAA) of styrenes provides a powerful disconnection for pharmacologically relevant γ-arylamines, but current methods cannot utilize unprotected primary alkylamines as feedstocks. Metal-catalyzed HAA protocols are also highly sensitive to α-substitution on the amine partner, and no catalytic solutions exist for α-tertiary γ-arylamine synthesis via this approach. We report a solution to these problems using organophotoredox catalysis, enabling a direct, modular, and sustainable preparation of α-(di)substituted γ-arylamines, including challenging electron-neutral and moderately electron-rich aryl groups. A broad range of functionalities are tolerated, and the reactions can be run on multigram scale in continuous flow. The method is applied to a concise, protecting-group-free synthesis of the blockbuster drug Fingolimod, as well as a phosphonate mimic of its in vivo active form (by iterative α-C–H functionalization of ethanolamine). The reaction can also be sequenced with an intramolecular N -arylation to provide a general and modular access to valuable (spirocyclic) 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydronaphthyridines. Mechanistic and kinetic studies support an irreversible hydrogen atom transfer activation of the alkylamine by the azidyl radical and some contribution from a radical chain. The reaction is photon-limited and exhibits a zero-order dependence on amine, azide, and photocatalyst, with a first-order dependence on styrene.

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“… Fairhurst et al (2020) reported the discovery of FGF401 (roblitinib) as a potent, selective FGFR4 inhibitor. Through high throughput screening, 2-formylquinoline amide (2-FQA) derivatives were identified as the starting hits.…”

Section: Small-molecule Fgfr Inhibitorsmentioning

confidence: 99%

Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review

Zheng

Zhang

et al. 2022

Front. Chem.

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Targeted therapy is a groundbreaking innovation for cancer treatment. Among the receptor tyrosine kinases, the fibroblast growth factor receptors (FGFRs) garnered substantial attention as promising therapeutic targets due to their fundamental biological functions and frequently observed abnormality in tumors. In the past 2 decades, several generations of FGFR kinase inhibitors have been developed. This review starts by introducing the biological basis of FGF/FGFR signaling. It then gives a detailed description of different types of small-molecule FGFR inhibitors according to modes of action, followed by a systematic overview of small-molecule-based therapies of different modalities. It ends with our perspectives for the development of novel FGFR inhibitors.

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Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4

Cited by 79 publications

References 78 publications

Discovery of novel therapeutic targets in cancer using patient-specific gene regulatory networks

Discovery of novel therapeutic targets in cancer using patient-specific gene regulatory networks

Photocatalytic Hydroaminoalkylation of Styrenes with Unprotected Primary Alkylamines

Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review

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