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 which was itself acquired by Amgen in 2013) where the addition of a morpholino cap (to increase solubility) generated Carfilzomib.


Relevant Publications

From epoxomicin to carfilzomib:chemistry, biology, and medical outcomes.
Kim KB, Crews CM
Natural Product Reports 2013. 30(5):600-604

Proteasome Inhibitors.
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

Natural Product Inhibitors of the Ubiquitin-Proteasome Pathway.
Schneekloth JS JR., Crews CM
Curr Drug Targets 2011.  12(11):1581-1594

Proteasome Inhibitors in Cancer Chemotherapy.
Molineaux CJ, Crews CM
Cancer, Principles; Practice of Oncology , 8th Edition (Eds: VT Devita, TS Lawrence and SA Rosenberg) 2008.  Chapter 25:486-490

The Ubiquitin-proteasome Pathway and Proteasome Inhibitors.
Myung J, Kim K, Crews CM
Medicinal Research Reviews 2001. 21(4):245-273

Crystal Structure of Epoxomicin: 20S Proteasome Reveals a Molecular Basis for Selectivity of α’, β’ -Epoxyketone Proteasome Inhibitors.
Groll M, Kim K, Kairies N, Huber R, Crews CM
Am. Chem. Soc. 2000. 122:1237-1238

Proteasome Inhibition by the Natural Products Eponemycin and dihydroeponemycin: Insights into Specificity and Potency.
Kim K, Myung J, Sin N, Crews CM
Bioorg. Med. Chem. Lett. 1999.  9(23):3335-3340

Towards Subunit specific Proteasome Inhibitors: Synthesis and Evaluation of Peptide α’, β’-epoxyketones.
Elofsson M, Splittgerber U, Myung J, Crews CM
Chemistry; Biology 1999.  6(11):811-822.

Epoxomicin, a Potent and Selective Proteasome Inhibitor exhibits in vivo Anti-inflammatory Activity.
Meng L, Mohan R, Kwok BHK, Elofsson M, Sin N, Crews CM
Proc. Natl. Acad. Sci. USA 1999.  96(18):10403-10408

Total Synthesis of the Potent Proteasome Inhibitor Epoxomicin: A Potential Tool for Understanding Proteasome Biology.
Sin N, Kim KB, Elofsson M, Meng L, Auth H, Kwok BHB, Crews CM
Bioorganic; Med. Chem. Letters 1999.  9(15):2283-8