PF-6683324 is a Potent Pan-Trk Inhibitor

2022-07-15

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.

Reference:

[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.