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.

Relevant Publications:

Kim K, Myung J, Sin N, Crews CM
Bioorg. Med. Chem. Lett. 1999 9 23 3335-3340
Elofsson M, Splittgerber U, Myung J, Crews CM
Chemistry & Biology 1999 6 11 811-822
Meng L, Mohan R, Kwok BHK, Elofsson M, Sin N, Crews CM
Proc. Natl. Acad. Sci. USA 1999 96 18 10403-10408
Sin N, Kim KB, Elofsson M, Meng L, Auth H, Kwok BHB, Crews CM
Bioorganic & Med. Chem. Letters 1999 9 15 2283-2288