Abstract
The neurotrophic receptor tyrosine kinase (NTRK) genes including NTRK1, NTRK2, and NTRK3 encode the tropomyosin receptor kinase (Trk) proteins TrkA, TrkB, and TrkC, respectively. So far, two TRK inhibitors, larotrectinib sulfate (LOXO-101 sulfate) and entrectinib (NMS-E628, RXDX-101), have been approved for clinical use in 2018 and 2019, respectively. To overcome acquired resistance, next-generation Trk inhibitors such as selitrectinib (LOXO-195) and repotrectinib (TPX-0005) have been developed and exhibit effectiveness to induce remission in patients with larotrectinib treatment failure. Herein, we report the identification and optimization of a series of macrocyclic compounds as potent pan-Trk (WT and MT) inhibitors that exhibited excellent physiochemical properties and good oral pharmacokinetics. Compound 10 was identified via optimization from the aspects of chemistry and pharmacokinetic properties, which showed good activity against wild and mutant TrkA/TrkC in in vitro and in vivo studies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Aza Compounds / chemical synthesis
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Aza Compounds / chemistry
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Aza Compounds / pharmacology*
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Screening Assays, Antitumor
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Female
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Humans
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Macrocyclic Compounds / chemical synthesis
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology*
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Male
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / metabolism
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Receptor, trkA / antagonists & inhibitors
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Receptor, trkA / metabolism
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Receptor, trkB / antagonists & inhibitors
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Receptor, trkB / metabolism
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Receptor, trkC / antagonists & inhibitors
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Receptor, trkC / metabolism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Aza Compounds
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Macrocyclic Compounds
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Membrane Glycoproteins
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NTRK1 protein, human
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NTRK3 protein, human
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Protein Kinase Inhibitors
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Pyrazoles
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repotrectinib
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selitrectinib
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Receptor, trkA
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Receptor, trkB
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Receptor, trkC
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tropomyosin-related kinase-B, human