An old drug brings about a novel technology

Degrading proteins as opposed to inhibiting them has potential to open up a novel area of drug development. I first wrote about the protein-clearing technology last month when Merck and Arvinas inked a $434 million deal. Last week, researchers at Dana-Farber Cancer Institute reported details in the latest issue of Science[1].

The authors attached JQ1, a BET inhibitor, to phthalimide, a derivative of thalidomide. The phthalimide was designed to bind to CRBN, part of an ubiquitin ligase complex. The resultant compound, dBET1, induced CRBN -dependent BET protein degradation.


They next treated leukemia cells (MV4;11) and lymphoma cells (DHL4) with dBET1. Marked degradation (76%) of the target protein was observed at 1 hour and complete degradation was observed at 2 hours of treatment. dBET1 induced an enhanced apoptotic response compared to JQ1.

The researchers then treated tumor-bearing mice with dBET1 (50 mg/kg). Degradation of the target protein was observed 4 hours after a first or second daily treatment. In mice model, dBET1 also resulted in improved anti-tumor efficacy compared to JQ1.

It is not uncommon that inhibiting a protein is not always functionally equivalent to knocking out the protein. The protein-clearing technology is a feasible approach to reproduce the phenotype of knockout.

[1] Science. 2015, doi: 10.1126/science.aab1433.


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