XIB4035, a novel nonpeptidyl small molecule agonist for GFRα-1

Tokugawa, Kimiko; Yamamoto, K.; Nishiguchi, Mariko; Sekine, Takumi; Sakai, Masahiko; Ueki, Tomokazu; Chaki, Shigeyuki; Okuyama, Shigeru

doi:10.1016/s0197-0186(02)00053-0

Cited by 34 publications

(33 citation statements)

References 29 publications

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“…Today, XIB4035, a 456.5 Da quinol binding to GFRα1, is the only available "ligand" of GFRα1 reported to induce RET autophosphorylation in Neuro-2A cells [82]. The molecule displaces GDNF from GFRα1 with an IC50 of 10 mM.…”

Section: Gfl Mimetics and Small Molecules Targeting The Gfls' Receptorsmentioning

confidence: 99%

“…Based on the previously discussed evidence of animal studies, and considering that GDNF has been demonstrated to undergo both retrograde and anterograde transport in neurons [10,31] it seems reasonable that, broadly-speaking, a GDNF-related therapy may be effective at both peripheral and central levels. In addition, as minimally invasive topical or systemic routes of administration other than the direct delivery into the central or the peripheral neurons have proved to be efficacious in animal models [4,64,[81][82][83], it seems desirable that these routes are explored in clinical settings too.…”

Section: Expert Opinionmentioning

confidence: 99%

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Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

Merighi

2015

Expert Opinion on Therapeutic Targets

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Introduction: GDNF and its family of ligands (GFLs) have several functions in the nervous system. As a survival factor for dopaminergic neurons, GDNF was used in clinical trials for Parkinson's disease. However, GFLs their receptors are potential targets for new pain-controlling drugs. Such a potential should not be underestimated because molecules with analgesic activities in rodents mostly failed to be effective in translational studies. Areas covered:The circuitry, molecular and cellular mechanisms by which GFLs control nociception, their intervention in inflammatory and neuropathic pain, the problems related to effective GDNF delivery to the brain, the possibility to target the GFL receptor complex rather than its ligands, also by the use of non-peptidyl agonists, are discussed. Expert opinion:In nociceptive pathways, an ideal drug should either: i. Target the release of endogenous GFLs from large dense-cored vesicles (LGVs) by acting e.g. onto the phosphatidylinositol-3-phosphate [PtdIns(3)P] pool, which is sensitive to Ca 2+ modulation; ii. Target the GFL receptor complex. Besides to XIB403, a thiol molecule that enhances GFRα family receptor signaling, existing drugs such as retinoic acid and amitriptyline should be considered for effective targeting of GDNF, at least in neuropathic pain. The approach of pain modeling in experimental animals is discussed.

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Section: Gfl Mimetics and Small Molecules Targeting The Gfls' Receptorsmentioning

confidence: 99%

Section: Expert Opinionmentioning

confidence: 99%

Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

Merighi

2015

Expert Opinion on Therapeutic Targets

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“…In the present study, we tested whether GDNF skin overexpression or topical application of XIB4035, a reported nonpeptidyl small-molecule agonist for GFRα1 (20), could be used to treat two mouse models of progressive SFN. We found that GDNF skin overexpression and topical XIB4035 are equally effective in treating SFN caused by dysfunction of nonmyelinating Schwann cells and that topical XIB4035 treatment also ameliorates SFN symptoms in a mouse model of diabetic SFN.…”

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confidence: 99%

Treating small fiber neuropathy by topical application of a small molecule modulator of ligand-induced GFRα/RET receptor signaling

Hedstrom

Murtie

Albers

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Small-fiber neuropathy (SFN) is a disorder of peripheral nerves commonly found in patients with diabetes mellitus, HIV infection, and those receiving chemotherapy. The complexity of disease etiology has led to a scarcity of effective treatments. Using two models of progressive SFN, we show that overexpression of glial cell line-derived neurotrophic factor (GDNF) in skin keratinocytes or topical application of XIB4035, a reported nonpeptidyl agonist of GDNF receptor α1 (GFRα1), are effective treatments for SFN. We also demonstrate that XIB4035 is not a GFRα1 agonist, but rather it enhances GFRα family receptor signaling in conjunction with ligand stimulation. Taken together, our results indicate that topical application of GFRα/RET receptor signaling modulators may be a unique therapy for SFN, and we have identified XIB4035 as a candidate therapeutic agent.topical drug | pain | thermonociception | sensory | trophic factor S mall-fiber neuropathy (SFN), i.e., damage or dysfunction of small-diameter axons (C fibers) in peripheral nerves, is a prevalent neurological disorder that afflicts an estimated 1.5% of the world's population and millions of people in the United States (1-3). SFN is associated with diabetes, HIV infection, and chemotherapy treatment, but many patients suffer from idiopathic SFN (3-5). SFN patients can exhibit a large variety of symptoms, including loss of sensation and chronic pain. Despite the pervasiveness of SFN, its etiology is poorly understood, resulting in a lack of disease-modifying treatments.Initial stages of SFN commonly involve nerve terminal degeneration before sensory neuron death (6), and reduction in targetderived trophic factor expression has been observed in multiple models of peripheral neuropathy (7,8). Therefore, replenishing or replacing neurotrophic factors promptly after disease onset could potentially be used as a treatment to promote the survival and restore the function of C-fiber neurons (9, 10). One group of trophic factors necessary for development and survival of C fibers is the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) (10, 11). Each family member interacts selectively with a different high affinity receptor: GDNF with GDNF receptor α1 (GFRα1), neurturin (NRTN) with GFRα2, artemin (ARTN) with GFRα3, and persephin (PSPN) with GFRα4, although GDNF and NRTN have the capacity to bind and activate GFRα2 and GFRα1, respectively (12). Each ligand/receptor pair forms a complex with the RET receptor tyrosine kinase, resulting in downstream effects that include tyrosine hydroxylase (TH) gene transcription (13,14). GFLs not only play a pivotal role in sensory neuron development, but also appear to be beneficial in the context of peripheral nerve injury. For example, systemic, transgenic, or viral delivery of GFLs has been shown to attenuate neuropathic symptoms in mouse models of nerve injury (15-19). Thus, we hypothesized that topical delivery of GDNF receptor agonists to the skin would be an effective, noninvasive therapeutic approach for t...

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“…Therefore, in addition to a therapeutic tool itself, GDNF constitutes also a target for the development of new therapeutics. Interestingly, it was suggested that XIB4035, a nonpeptidyl small molecule that acts as a GFR 1 agonist and mimics the neurotrophic effects of GDNF in Neuro-2A cells, might have beneficial effects for the treatment of PD (Tokugawa et al, 2003). Leucine-isoleucine (Leu-Ile), a hydrophobic dipeptide that partially resembles the site on FK506 that binds to immunophilin (Schreiber, 1991), significantly increases GDNF and BDNF levels in the conditioned medium from cultured hippocampal neurons, and protects both dopaminergic and non-dopaminergic neurons from natural cell death in low density cultures (Nitta et al, 2004).…”

Section: Inducing Endogenous Gdnf Expression/signalingmentioning

confidence: 99%