Small-Molecule Trk Agonists: Where Do We Go from Here?

Abstract

About two decades ago, there were no validated, agonistic small-molecule modulators of Trk (tropomyosin receptor kinase). High-throughput screening of commercial libraries seemed an attractive way to identify starting structures when the research community became aware of their potential for treatment of neurodegeneration and traumatic injuries (e.g., stroke) because this strategy avoids high-level chemical expertise for molecular design and synthesis. Cost and effort constraints arising from library acquisition and assays imposed limitations on numbers of compounds tested, so filtering to reduce library sizes before screening was routine. One of the criteria was to prioritize existing pharmaceuticals because these had known toxicity profiles and side effects, at least in some delivery and dosing regimens, and many cases had proven blood brain barrier (BBB) permeabilities. This review gives our perspective on how these efforts transpired, lessons learned, and constraints which hold back development in this area at the present time.

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(a) Neurotrophins are dimeric (gray) and interact selectively with their primary targets (black arrows) but also show cross-reactivity with other Trks (broad dashed line). All the Neurotrophins interact with p75 (thin dashed line). (b) Some mechanisms by which monomeric small molecules might activate Trk receptors.

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(a) NGF interaction with the extracellular domain of TrkA (PDB 2IFG). (b) NGF interacting with the extracellular domain of p75 (PDB 1SG1).

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Most widely studied small molecule leads for Trk agonism. Reported Trk selectivities in blue, outline of observations in green, and potential issues in red.

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Workflow of the enzyme-linked fixed-cell immunoassay.

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(a) Molecular modeling of the inactive open conformation, and the active closed one. AXXXG is the region where the two helices contact each other. (b) Structures of the featured antidepressants. (c) Fluoxetine modeled in the crevice between the TrkB transmembrane helices. (d) Rat hippocampal neurons transfected with TrkB.GFP immediately after photobleaching (center) and 2 min later (right): A untreated, B BDNF-treated, C fluoxetine-treated, or D ketamine-treated. Created by modifying open source graphics in the featured Cell paper, https://doi.org/10.1016/j.cell.2021.01.034.

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Structural similarities between cholesterol and putative TrkB agonists.

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Structural similarities between psychedelics and antidepressants that bind the TrkB transmembrane domain and putative TrkB agonists.

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Lessons from studies on small-molecule Trk modulator candidates.