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 KB, Crews CM
Natural Product Reports 2013 30 5 600-604
Kauffman MG, Molineaux CJ, Kirk CJ, Crews CM
Cancer: Principles & Practice of Oncology (Eds., Devita VT, Lawrence TS, Rosenberg SA, DePinho RA) 2011 Chapter 41 441-449
Schneekloth JS JR., Crews CM
Curr Drug Targets 2011 12 11 1581-1594
Molineaux CJ, Crews CM
Cancer, Principles & Practice of Oncology (Eds: VT Devita, TS Lawrence and SA Rosenberg) 2008 8th Edition Chapter 25 486-490
Myung J, Kim K, Crews CM
Medicinal Research Reviews 2001 21 4 245-273