Small molecule stalls PCSK9 translation

Last week, Pfizer announced it would stop work on bococizumab, a monoclonal antibody designed to inhibit the cholesterol regulator proprotein convertase subtilisin/kexin type 9 (PCSK9) because of weak data and a changing market for lipid-lowering agents (see page 15). The news came just one week after Pfizer scientists, led by Robert Dullea, reported a small molecule that can shut down translation of PCSK9 (bioRxiv 2016, DOI: 10.1101/083097). The work, which appeared on a preprint server and has not yet been peer reviewed, was done in collaboration with University of California, Berkeley, researchers led by Jamie Cate. The small molecule, known as PF-06446846, appears to cause the ribosome to stall when synthesizing PCSK9. “PF-06446846 is exceptionally specific, affecting very few proteins,” the researchers note. The compound lowered cholesterol levels in rats. PCSK9 prevents the receptors that remove low-density lipoprotein cholesterol—also known as LDL or “bad” cholesterol—from doing their job. Two monoclonal antibody drugs that block PCSK9 have been approved to lower LDL cholesterol in certain patients, but to date, no small molecule aimed at lowering PCSK9 has been approved. This study, the authors write, “reveals a previously unexpected tunability of the human ribosome, which allows small molecules to specifically block translation of individual transcripts.”