| Description: |
In vitro:
PF-06273340 is a highly potent pan-Trk inhibitor, with an excellent LipE profile. PF-06273340 is profiled in a series of in vitro safety assays, showing little cytotoxicity in THLE or HepG2 cell lines (IC50 > 42 μM and >300 μM, respectively). In this broad panel, all IC50/Ki values were >10 μM except for COX-1 (IC50 = 2.7 μM) and dopamine transporter assays (Ki = 5.2 μM) and PDEs 4D, 5A, 7B, 8B, and 11 (54−89% inhibition at 10 μM). PF-06273340 is screened in the Invitrogen wide kinase panel of 309 kinases, and all were inhibited by <40% when tested at 1 μM except the following: MUSK (IC50 53 nM), FLT-3 (IC50 395 nM), IRAK1 (IC50 2.5 μM), MKK (90% @ 1 μM), and DDR1 (60% @ 1 μM).
In vivo: In rats, decreases in white blood cell count are observed from 150 mg/kg/day. At doses ≥250 mg/kg, increases in body weight gain and food consumption are observed, effects that could be rationalized as being mediated by central inhibition of TrkB, agonists of which are known to be anorexigenic in rodents. Adaptive changes in the liver are observed microscopically and accompanied by increased liver weight at ≥250 mg/kg and increases cholesterol at 1000 mg/kg. Overall, PF-06273340 is well tolerated up to 1000 mg/kg/day where plasma exposure (unbound Cavg) is approximately 400×TrkA IC50. |
