Merck bets $434 million on protein-clearing technology

When we find a disease-causing protein, the first thing would be finding a small molecule or an antibody to inhibit it. Professor Craig Crews at Yale University has another idea —- directly degrade the disease-causing proteins.

Crews’ technology, known as PROTAC (proteolysis-targeting chimaera), is building on a natural process where proteins are tagged for degradation by ubiquitin. PROTACs are bifunctional small molecules that bridge target proteins to E3 ubiquitin ligase, labelling it for degradation.

PROTAC

Source: ACS Chem Biol. 2008, 3(11), 677-692.

Crews lab has created various PROTACs targeting cancer-promoting proteins including MetAP-2[1], AR[2], ER, FRS2α[3] and PI3K.

In 2012, Yale licensed patents on PROTACs to GlaxoSmithKline to pursue undisclosed cancer targets. In September 2013, Arvinas was established with a $15 million A round from Canaan Partners and 5AM Ventures, to commercialize Crews’ PROTAC technology. Merck and Arvinas inked a $434 million deal on April 7, 2015.

I don’t see PROTACs as a practical drug class to date because of its relatively mild biological activity. Knockdown of PI3K in MCF-7 cells needs 20-40 µM concentrations of PROTAC. Anti-PI3K PROTAC only demonstrated a moderate anti-tumor effect in ovarian cancer mice[3]. Wait for better preclinical results.

[1] Proc Natl Acad Sci USA. 2001, 98(15), 8554-8559.

[2] Mol Cell Proteomics. 2003, 2(12), 1350-1358.

[3] Proc Natl Acad Sci USA. 2013, 110(22), 8942-8947.

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