Stalling translation

How Pfizer’s translation-blocking small molecules inhibit tough targets

Pfizer Inc. has discovered a mechanism to create small molecule inhibitors of PCSK9 by halting translation of the protein as it emerges from the ribosome. While the company is remaining tight-lipped about that program, it believes the strategy will have important ramifications for other targets that have proven intractable for oral drug development.

Last month, Pfizer published a study in PLoS Biology describing the identification of PF-06446846, a small molecule that blocks translation of PCSK9 by binding the ribosomal complex and blocking its exit tunnel.

The work was the product of a six-year collaboration between Pfizer scientists and University of California Berkeley professors Jennifer Doudna and Jamie Cate, who brought structural biology, RNA and ribosome expertise to the partnership.

“People are trying to find inhibitors for lots of targets out there. Our idea is to prevent the protein from being made in the first place. This mechanism could apply to so many proteins,” said Bob Dullea, director in the internal medicine research unit of Pfizer.

The study adds to an emerging trend in industry and academia of tackling challenging protein targets by hitting them before they are translated from RNA.

“Our idea is to prevent the protein from being made in the first place. This mechanism could apply to so many proteins.”

Bob Dullea, Pfizer

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