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Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain.

Ahmed MS, Wang P, Nguyen NUN, Nakada Y, Menendez-Montes I, Ismail M, Bachoo R, Henkemeyer M, Sadek HA, Kandil ES
Proc Natl Acad Sci U S A 118 (2021)
Related entries: 6umw, 7kpm

Cited: 7 times
EuropePMC logo PMID: 33627480

Abstract

Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.

Articles - 7kpl mentioned but not cited (1)

  1. Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain. Ahmed MS, Wang P, Nguyen NUN, Nakada Y, Menendez-Montes I, Ismail M, Bachoo R, Henkemeyer M, Sadek HA, Kandil ES. Proc Natl Acad Sci U S A 118 e2016265118 (2021)


Reviews citing this publication (3)

  1. Drug Repurposing to Target Neuroinflammation and Sensory Neuron-Dependent Pain. Sisignano M, Gribbon P, Geisslinger G. Drugs 82 357-373 (2022)
  2. Antimicrobial therapies for chronic pain (part 2): the prevention and treatment of chronic pain. Wang EJ, Dolomisiewicz E, Karri J, Tontisirin N, Cohen SP. Korean J Pain 36 299-315 (2023)
  3. Ephs in cancer progression: complexity and context-dependent nature in signaling, angiogenesis and immunity. Guo X, Yang Y, Tang J, Xiang J. Cell Commun Signal 22 299 (2024)

Articles citing this publication (3)

  1. Hit Identification of a Novel Quinazoline Sulfonamide as a Promising EphB3 Inhibitor: Design, Virtual Combinatorial Library, Synthesis, Biological Evaluation, and Docking Simulation Studies. Lee K, Nada H, Byun HJ, Lee CH, Elkamhawy A. Pharmaceuticals (Basel) 14 1247 (2021)
  2. FDA approved drugs with antiviral activity against SARS-CoV-2: From structure-based repurposing to host-specific mechanisms. Ahmed MS, Farag AB, Boys IN, Wang P, Menendez-Montes I, Nguyen NUN, Eitson JL, Ohlson MB, Fan W, McDougal MB, Mar K, Thet S, Ortiz F, Kim SY, Solmonson A, Williams NS, Lemoff A, DeBerardinis RJ, Schoggins JW, Sadek HA. Biomed Pharmacother 162 114614 (2023)
  3. Identification of FDA-approved drugs that induce heart regeneration in mammals. Ahmed MS, Nguyen NUN, Nakada Y, Hsu CC, Farag A, Lam NT, Wang P, Thet S, Menendez-Montes I, Elhelaly WM, Lou X, Secco I, Tomczyk M, Zentilin L, Pei J, Cui M, Dos Santos M, Liu X, Liu Y, Zaha D, Walcott G, Tomchick DR, Xing C, Zhang CC, Grishin NV, Giacca M, Zhang J, Sadek HA. Nat Cardiovasc Res 3 372-388 (2024)


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