Background & Aims
Negative allosteric modulators (NAMs) targeting Tropomyosin receptor kinase A (TrkA), a pivotal receptor in neurotrophin signaling, represent a promising avenue in therapeutic intervention. By binding to a site distinct from the active site on TrkA [1-3], NAMs offer a unique approach to attenuate TrkA signaling without directly interfering with the levels of NGF. This modulation holds potential for treating conditions associated with aberrant NGF or TrkA signaling, such as chronic pain conditions. We have during a lead optimization program previously described analgesic and anti-inflammatory effects of TrkA-NAMs, shedding light on the mechanism of action, therapeutic implications, and the prospects this class of molecules hold for addressing unmet medical needs. The aim of the present study was to evaluate the clinical candidate ACD137, a novel TrkA-NAM molecule, for its pharmacological effects in various in vitro and in vivo models.
Methods
Results
Conclusions
TrkA-NAM’s have shown promise in both neuropathic and nociceptive models. Enhanced pain relief is attributed to the inhibition of NGF/TrkA signaling, attenuating peripheral sensitization and inflammation. Identification of selective and potent TrkA-NAM’s could potentially avoid some of the side effects observed for anti-NGF antibodies. ACD137 has previously demonstrated analgesic and anti-inflammatory effects using Hargreave’s test [4]. The crystal structure determination and the competition with the active-site directed probe, suggests that binding of TrkA-NAM’s to the allosteric site induces a conformational change resulting in reduced affinity of TrkA towards ATP. The present study clarifies the mechanism of action and supports the analgesic effect of ACD137 in relevant preclinical models of pain. Overall, TrkA-NAM’s demonstrate potential as a novel therapeutic approach for alleviating different types of pain, highlighting their role in advancing pain management strategies.
References
Presenting Author
Märta Segerdahl
Poster Authors
Pontus Forsell
Alzecure Pharma AB
Lead Author
Gunnar Nordvall
PhD
Alzecure Pharma AB
Lead Author
Maria Backlund
PhD
Alzecure Pharma AB
Lead Author
Veronica Lidell
MSc
Alzecure Pharma AB
Lead Author
Cristina Parrado-Fernandez
PhD
Alzecure Pharma AB
Lead Author
Johan Sandin
PhD
Alzecure Pharma AB
Lead Author
Märts Segerdahl
MD, PhD
Alzecure Pharma AB
Lead Author