PF-6683324 is a Potent Pan-Trk Inhibitor

Tropomyosin receptor kinases (Trk) family includes TrkA, TrkB and TrkC, can be activated by hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Kinds of research prove that TrkA is a new target for pain, TrkB is associated with obesity and development by human genetic data, and TrkC plays a role in the development and survival of the sympathetic nervous system.

Therefore, the discovery of pan-Trk inhibitors becomes a new target for pain research.

PF-6683324 is a potent pan-Trk inhibitor with IC50s of 1.9 nM, 2.6 nM and 1.1 nM for TrkA, TrkB and TrkC, respectively. PF-6683324 (1 mg/kg; PO and IV, single dosage) exhibits low systemic clearance (CL) and moderate oral bioavailability (52%) in rats. In UV irradiation-induced hyperalgesia rat models, PF-6683324 (0.03, 0.32, and 3 mg/kg; PO, single dosage) significantly reverses hyperalgesia at 0.32, and 3 mg/kg after 1-6 hours of administration. Thus, it has anti-inflammatory activity and relieving pain effects. In general, these properties indicates that pan-Trk inhibitor PF-6683324 has the potential to become an oral medicine for chronic pain and is probably expects to translate to human.

In addition, PF-6683324 also inhibits protein tyrosine kinase 6 (PTK6) which is frequently detected in epithelial cancers. This agent has potent inhibitory activity against PTK6 with an IC50 of 76 nM and against p-PTK6 in engineered HEK293T cells over-expressing PTK6 WT with an IC50 of 0.70 μM. PF-6683324 can moderately suppress tumor cell growth. Therefore, PF-6683324 also has inhibitory activity against PTK6-associated cancer.

In conclusion, PF-6683324 is a potent pan-Trk inhibitor, and also inhibits PTK6 kinase, has the potential for researching painful inflammation and anticancer.


[1] Bagal SK, et al. J Med Chem. 2018 Aug 9;61(15):6779-6800.

[2] Qiu L, et al. PLoS One. 2018 Jun 7;13(6):e0198374.

[3] Gilic MB, et al. Biochim Biophys Acta Rev Cancer. 2020 Dec;1874(2):188432.