Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047)

…, GJ Laidig, ER Lewis, Y Lu, T Muchamuel…

Index: Zhou, Han-Jie; Aujay, Monette A.; Bennett, Mark K.; Dajee, Maya; Demo, Susan D.; Fang, Ying; Ho, Mark N.; Jiang, Jing; Kirk, Christopher J.; Laidig, Guy J.; Lewis, Evan R.; Lu, Yan; Muchamuel, Tony; Parlati, Francesco; Ring, Eileen; Shenk, Kevin D.; Shields, Jamie; Shwonek, Peter J.; Stanton, Timothy; Sun, Congcong M.; Sylvain, Catherine; Woo, Tina M.; Yang, Jinfu Journal of Medicinal Chemistry, 2009 , vol. 52, # 9 p. 3028 - 3038

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Citation Number: 162

Abstract

Proteasome inhibition has been validated as a therapeutic modality in the treatment of multiple myeloma and Non-Hodgkin's lymphoma. Carfilzomib, an epoxyketone currently undergoing clinical trials in malignant diseases, is a highly selective inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. A chemistry effort was initiated to discover orally bioavailable analogues of carfilzomib, which would have potential for ...