Novel drug-like, non-covalent, and reversible proteasome inhibitors with an oxadiazole-isopropylamide core have been identified. These are inhibitors for proteasome chymotrypsin-like (CT-L) activity. The most promising molecule inhibits CT-L activity with an IC50 of 32 nM in vitro and an IC50 of 1 Î¼M in MDA-MB-468 human breast cancer cells. Two further promising analogs inhibit CT-L activity in vitro with IC50âs of 39 nM and 32 nM.
- Proteasome inhibition is a validated approach to cancer therapy, as shown by the FDA approval of Velcade for the treatment of multiple myeloma and relapsed mantle cell lymphoma. Velcade is a dipeptidyl boronic acid that is also a reversible inhibitor of CT-L activity by a different mechanism of action.
- Velcade had approximately $700 million in sales in the US alone in 2011, is approved in more than 90 countries, and is sold by Millennium: The Takeda Oncology Company.
- An attractive market as evidenced by the other proteasome inhibitors in clinical development includes MLN9708 (a second-generation proteasome inhibitor also from Millennium), CEP-1877 (Cephalon—acquired by Teva), Carfilzomib (Onyx Pharmaceuticals), and NPI-0052 (Nereus Pharmaceuticals).