Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain
Fig 2
Oral administration of PF-06446846 reduces plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) and total cholesterol levels in rats.
(A–B) Plasma PCSK9 levels following (A) a single and (B) 12 daily oral doses of PF-06446848. Rats were administered the indicated dose of PF-06446846, and plasma concentrations of PCSK9 were measured by commercial ELISA at 1, 3, 6, and 24 h after dosing (A) or the 12th daily dose (B). Symbols represent mean concentration ± standard error and were jittered to provide a clearer graphical representation. Data were analyzed using a mixed model repeated measure (MMRM) with treatment, day, and hour as fixed factors; treatment by day and hour as an interaction term; and animal as a random factor. The significance level was set at a level of 5%. No adjustment for multiple comparisons was used. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001. (C–E) Total plasma (C), low-density lipoprotein (LDL) (D), and high-density lipoprotein (HDL) (E) cholesterol levels in rats measured 24 h following 14 daily oral doses of PF-06446846. Symbols represent individual animal values. The middle horizontal bar represents the group mean ± standard deviation. Difference between group means relative to vehicle was performed by a one-way ANOVA followed by a Dunnett’s multiple comparisons test; * p ≤ 0.05, **** p ≤ 0.0001. The individual quantitative observations that underlie Fig 2 are in S14 Table.