PF-06446846 Hydrochloride is the hydrochloride salt of a small molecule that suppresses synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9). Its activity stems from selective ribosome stalling during protein production, rather than direct inhibition of circulating PCSK9. The salt is registered under CAS 1632250-50-0.
Application of PF-06446846 Hydrochloride
Researchers use the Pfizer PF-06446846 Hydrochloride probe to investigate how small molecules inhibit translation in a nascent-chain-dependent manner. PCSK9 reporters and peptide-sequence variants help identify features that confer sensitivity, while ribosome profiling locates stalls and detects effects on other transcripts.
For lipid research, oral rodent studies allow PCSK9 suppression to be assessed alongside cholesterol changes. Combining these approaches helps distinguish the intended biochemical effect from broader changes in protein production and tolerability.
In Vitro
PF-06446846 inhibited PCSK9 secretion from Huh7 cells with an IC50 of 0.3 µM. In a HeLa cell-free system, a PCSK9(1–35)-luciferase reporter gave an IC50 of 2 µM. Binding to purified human ribosomes yielded a Kd of 7 µM. These values measure different endpoints and should not be compared as equivalent potency estimates.
Ribosome profiling identified additional susceptible transcripts. SILAC proteomics showed no general effect on intracellular or secreted protein output under the tested conditions, supporting selective rather than global inhibition of translation.
In Vivo
Male Sprague-Dawley rats received 5, 15 or 50 mg/kg orally each day for 14 days. Plasma PCSK9 decreased dose-dependently after single and repeated dosing. At 50 mg/kg, total cholesterol fell by approximately 30% and LDL cholesterol by 58%, without a significant decrease in HDL cholesterol.
At the highest dose, bone marrow changes, a 9% reduction in red cell mass and lower lymphocyte counts were also observed. The authors identified the narrow margin between PCSK9 lowering and hematopoietic effects as a likely obstacle to clinical development.
Biochemical and Physiological Actions
The PF-06446846 Hydrochloride molecular structure contains an R-configured piperidine group and a substituted benzamide scaffold. The active molecule binds within the ribosomal exit tunnel, altering the path of susceptible nascent chains and impeding elongation. During PCSK9 synthesis, ribosome accumulation centers near codon 34.
Sensitivity depends primarily on the growing peptide's amino acid sequence, rather than its mRNA sequence. Lower PCSK9 production can reduce LDL receptor degradation, helping preserve receptor-mediated clearance of circulating LDL.
Features and Benefits of PF-06446846 Hydrochloride
The PF-06446846 Hydrochloride molecular weight is approximately 470.35 g/mol, compared with 433.89 g/mol for the free base. Use the value corresponding to the supplied salt when calculating molar stock concentrations.
Published reporter, ribosome-profiling and animal data provide complementary reference endpoints for experimental design. When confirming the PF-06446846 Hydrochloride structure, check both the R stereochemistry and hydrochloride component. Consult the batch documentation for purity and establish solubility under the intended preparation conditions.
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