Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models

Albaugh, Pam; Fan, Yi; Mi, Yuan; Sun, Fangxian; Adrián, Francisco; Li, Nanxin; Jia, Yong; Sarkisova, Yelena; Kreusch, Andreas; Hood, Tami; Lu, Min; Liu, Guoxun; Huang, Shenlin; Liu, Zuosheng; Loren, Jon C.; Tuntland, Tove; Karanewsky, Donald S.; Seidel, H. Martin; Molteni, Valentina

doi:10.1021/ml200261d

Cited by 90 publications

(85 citation statements)

References 27 publications

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“…No examples were seen of TKDs that pack like Ror2, but close relatives of one of the TrkA crystallographic dimers were seen both in inhibitor-bound TrkC (PDB code 3V5Q [33]) and eight PDB entries describing structures of the inactive TKD from FGFR1. This crystallographic TrkA dimer is shown in Figure 5(A).…”

Section: Resultsmentioning

confidence: 99%

Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family

Artim

Mendrola

Lemmon

2012

Biochemical Journal

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To investigate the range of autoinhibitory mechanisms used by TKDs (tyrosine kinase domains) from the insulin receptor family of RTKs (receptor tyrosine kinases), we determined crystal structures of TKDs from TrkA (tropomyosin receptor kinase A, a nerve growth factor receptor) and Ror2 (receptor tyrosine kinase-like orphan receptor 2, an unconventional Wnt receptor). TrkA autoinhibition closely resembles that seen for the insulin receptor, relying on projection of an activation loop tyrosine residue into the substrate-binding site and occlusion of the ATP-binding site by the activation loop. Ror2 employs similar mechanisms, but the unusual replacement of the phenylalanine residue in its Asp-Phe-Gly motif with leucine necessitates occlusion of the ATP-binding site by other means. The unusual Asp-Leu-Gly motif in Ror2 is displaced compared with other inactive kinases, allowing the activation loop to interact directly with the TKD's αC helix, in another mode of autoinhibition that is characteristic of the other extreme of this receptor family: ALK (anaplastic lymphoma kinase) and Met. These findings provide insight into the expected range of activating mutations in these TKDs in cancer. We also describe symmetrical dimers of the inactive TrkA TKD resembling those found in other RTKs, possibly reflecting an arrangement of kinase domains in a pre-formed TrkA dimer.

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Section: Resultsmentioning

confidence: 99%

Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family

Artim

Mendrola

Lemmon

2012

Biochemical Journal

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“…Therefore, we also tested the role of Trk signaling in C5a-induced thermal hyperalgesia. Because of the lack of commercially available isoform-selective Trk inhibitors McCarthy and Walker, 2014), we used a potent pan-Trk inhibitor, GNF-5837 (Albaugh et al, 2012), in these experiments. As a positive control, we demonstrated that pretreatment with GNF-5837 inhibited NGF-induced thermal hyperalgesia (Fig.…”

Section: Ngf Plays a Critical Role In C5a-induced Thermal Hyperalgesiamentioning

confidence: 99%

The Complement System Component C5a Produces Thermal Hyperalgesia via Macrophage-to-Nociceptor Signaling That Requires NGF and TRPV1

et al. 2016

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The complement cascade is a principal component of innate immunity. Recent studies have underscored the importance of C5a and other components of the complement system in inflammatory and neuropathic pain, although the underlying mechanisms are largely unknown. In particular, it is unclear how the complement system communicates with nociceptors and which ion channels and receptors are involved. Here we demonstrate that inflammatory thermal and mechanical hyperalgesia induced by complete Freund's adjuvant was accompanied by C5a upregulation and was markedly reduced by C5a receptor (C5aR1) knock-out or treatment with the C5aR1 antagonist PMX53. Direct administration of C5a into the mouse hindpaw produced strong thermal hyperalgesia, an effect that was absent in TRPV1 knock-out mice, and was blocked by the TRPV1 antagonist AMG9810. Immunohistochemistry of mouse plantar skin showed prominent expression of C5aR1 in macrophages. Additionally, C5a evoked strong Ca 2ϩ mobilization in macrophages. Macrophage depletion in transgenic macrophage Fas-induced apoptosis mice abolished C5a-dependent thermal hyperalgesia. Examination of inflammatory mediators following C5a injection revealed a rapid upregulation of NGF, a mediator known to sensitize TRPV1. Preinjection of an NGFneutralizing antibody or Trk inhibitor GNF-5837 prevented C5a-induced thermal hyperalgesia. Notably, NGF-induced thermal hyperalgesia was unaffected by macrophage depletion. Collectively, these results suggest that complement fragment C5a induces thermal hyperalgesia by triggering macrophage-dependent signaling that involves mobilization of NGF and NGF-dependent sensitization of TRPV1. Our findings highlight the importance of macrophage-to-neuron signaling in pain processing and identify C5a, NGF, and TRPV1 as key players in this cross-cellular communication.

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“…GNF5837 is a family-selective tyrosine kinase inhibitor 52, while the tyrosine kinase activity of the trkA receptor can be inhibited by GW441756 (p IC 50= 8.7, 86) and tyrphostin AG879 76.…”

Section: Type VII Rtks: Neurotrophin Receptor/trk Familymentioning

confidence: 99%

The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors

Alexander

Benson

Faccenda

et al. 2013

British J Pharmacology

151

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The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full.Catalytic receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets.It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.

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Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models

Cited by 90 publications

References 27 publications

Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family

Assessing the range of kinase autoinhibition mechanisms in the insulin receptor family

The Complement System Component C5a Produces Thermal Hyperalgesia via Macrophage-to-Nociceptor Signaling That Requires NGF and TRPV1

The Concise Guide to PHARMACOLOGY 2013/14: Catalytic Receptors

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