The Next Generation Proteasome Inhibitor Drug
In 1998, our lab starting developing what ultimately became Carfilzomib (Kyprolis™), the newly FDA-approved drug for relapsed multiple myeloma. This successful second-generation proteasome inhibitor is a soluble analog of YU101, a derivative of the microbially-derived natural product epoxomicin first synthesized by the our lab. Through systematic replacement of epoxomicin P2-P4 side chains (while retaining the proteasome-specific epoxyketone pharmacophore) we increased the potency and selectivity of YU101 several orders of magnitude over the parent natural product. YU101 subsequently served as the initial lead drug development candidate at newly founded Proteolix, Inc. (acquired by Onyx Pharmaceuticals in 2010) where the addition of a morpholino cap (to increase solubility) generated Carfilzomib.