Small-molecule kinase inhibitors: an analysis of FDA-approved drugs

Wu, Peng; Nielsen, Thomas E.; Clausen, Mads Hartvig

doi:10.1016/j.drudis.2015.07.008

Cited by 408 publications

(321 citation statements)

References 38 publications

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“…E7090 succinate associated more rapidly with FGFR1 than did ponatinib and E7090 dissociated more slowly and had a relatively longer resident time, than did AZD4547, which is a representative type I inhibitor. Our analysis revealed that E7090 possesses kinetic properties more similar to the type V inhibitors, such as lenvatinib, a VEGFR and multiple receptor tyrosine kinase inhibitor, which is the only type V kinase inhibitor approved for clinical use at this time (30). Further studies, including crystallization and costructural determination of the FGFR1-E7090 complexes, are required to fully understand the details of E7090 binding to FGFRs at the amino acid level.…”

Section: Discussionmentioning

confidence: 99%

“…We present the first evidence that the interaction of E7090 with FGFR1 has unique kinetics that is different from those of other selective FGFR inhibitors. More than 80% of approved kinase inhibitors possess the characteristics of either type I inhibitors or type II inhibitors (30). Selective FGFR inhibitors such as AZD4547 have been reported to possess the characteristics of type I inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models

Miyano

Yamamoto

Kodama

et al. 2016

Molecular Cancer Therapeutics

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The FGFR signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR. Furthermore, E7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. Our results suggest that E7090 is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. It is currently being investigated in a phase I clinical trial. Mol Cancer Ther; 15(11); 2630-9. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models

Miyano

Yamamoto

Kodama

et al. 2016

Molecular Cancer Therapeutics

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“…Trastuzumab, an inhibitor of the HER2 receptor tyrosine kinase (Slamon et al, 2001;Piccart-Gebhart et al, 2005;Romond et al, 2005;Force et al, 2007) was both the first monoclonal antibody TKI given FDA approval (in 1998) and the first TKI reported to cause cardiotoxicity (Wu et al, 2016). Since the reports of trastuzumab-induced toxicity, several additional targeted cancer therapeutics have been classified as cardiotoxic, observations that have contributed to the emergence of a new research field, cardio-oncology (Albini et al, 2010;Bellinger et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics

Shim

2018

Biophysical Journal

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Tyrosine kinase inhibitors (TKIs) are highly potent cancer therapeutics that have been linked with serious cardiotoxicity, including left ventricular dysfunction, heart failure, and QT prolongation. TKI-induced cardiotoxicity is thought to result from interference with tyrosine kinase activity in cardiomyocytes, where these signaling pathways help to control critical processes such as survival signaling, energy homeostasis, and excitation-contraction coupling. However, mechanistic understanding is limited at present due to the complexities of tyrosine kinase signaling, and the wide range of targets inhibited by TKIs. Here, we review the use of TKIs in cancer and the cardiotoxicities that have been reported, discuss potential mechanisms underlying cardiotoxicity, and describe recent progress in achieving a more systematic understanding of cardiotoxicity via the use of mechanistic models. In particular, we argue that future advances are likely to be enabled by studies that combine large-scale experimental measurements with Quantitative Systems Pharmacology (QSP) models describing biological mechanisms and dynamics. As such approaches have proven extremely valuable for understanding and predicting other drug toxicities, it is likely that QSP modeling can be successfully applied to cardiotoxicity induced by TKIs. We conclude by discussing a potential strategy for integrating genome-wide expression measurements with models, illustrate initial advances in applying this approach to cardiotoxicity, and describe challenges that must be overcome to truly develop a mechanistic and systematic understanding of cardiotoxicity caused by TKIs.

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“…Currently, there are about thirty small-molecule kinase inhibitors approved by the FDA but none of them exhibit selective binding to a unique kinase (24). Large-scale screening of known inhibitors has shown their promiscuity even to phylogenetically distant kinases (25).…”

Section: Introductionmentioning

confidence: 99%

“…The N-lobe has a Gly-rich GxGxxG motif called the Gly rich loop, which stabilizes the phosphates of the bound ATP molecule during catalysis. The activation loop is typically [20][21][22][23][24][25][26][27][28][29][30] residues in length beginning with a conserved DFG (almost always Asp-Phe-Gly, sometimes AspLeu-Gly or Asp-Trp-Gly) motif and extending up to an APE (Xxx-Pro-Glu, usually Ala-Pro-Glu) motif.…”

Section: Introductionmentioning

confidence: 99%

Clustering of the structures of protein kinase activation loops: A new nomenclature for active and inactive kinase structures

Modi

2018

Preprint

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Targeting protein kinases is an important strategy for intervention in cancer. Inhibitors are directed at the conserved active conformation or a variety of inactive conformations. While attempts have been made to classify these conformations, a structurally rigorous catalogue of states has not been achieved. The kinase activation loop is crucial for catalysis and begins with the conserved DFGmotif (Asp-Phe-Gly). This motif is observed in two major classes of conformations, DFGin -an ensemble of active and inactive conformations where the Phe residue is in contact with the C-helix of the N-terminal lobe, and DFGout -an inactive form where Phe occupies the ATP site exposing the C-helix pocket. We have developed a clustering of kinase conformations based on the backbone dihedral angles of the sequence X-D-F, where X is the residue before the DFGmotif, and the DFG-Phe side-chain rotamer, utilizing a density-based clustering algorithm. We have identified 8 distinct conformations and labeled them based on their Ramachandran regions (A=alpha, B=beta, L=left) and the Phe rotamer (minus, plus, trans). Our clustering divides the DFGin group into six clusters including 'BLAminus,' which contains active structures, and two common inactive forms, 'BLBplus' and 'ABAminus.' DFGout structures we have are predominantly in the 'BBAminus' conformation, which is essentially required for binding Type II inhibitors. Structural features such as the C-helix position and the overall activation loop conformation are strongly associated with our clusters. Our structurally intuitive nomenclature will aid in understanding the conformational dynamics of these proteins and structure-based development of kinase drugs.

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Small-molecule kinase inhibitors: an analysis of FDA-approved drugs

Cited by 408 publications

References 38 publications

E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models

E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models

Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics

Clustering of the structures of protein kinase activation loops: A new nomenclature for active and inactive kinase structures

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