Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047).
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 improved dosing flexibility and patient convenience over intravenously administered agents. The lead compound, 2-Me-5-thiazole-Ser(OMe)-Ser(OMe)-Phe-ketoepoxide (58) (PR-047), selectively inhibited CT-L activity of both the constitutive proteasome (beta5) and immunoproteasome (LMP7) and demonstrated an absolute bioavailability of up to 39% in rodents and dogs. It was well tolerated with repeated oral administration at doses resulting in >80% proteasome inhibition in most tissues and elicited an antitumor response equivalent to intravenously administered carfilzomib in multiple human tumor xenograft and mouse syngeneic models. The favorable pharmacologic profile supports its further development for the treatment of malignant diseases.
Proteolix, Inc., 333 Allerton Avenue, South San Francisco, California 94080, USA. hzhou@proteolix.com
Han-Jie
HJ
Zhou
Monette A
MA
Aujay
Mark K
MK
Bennett
Maya
M
Dajee
Susan D
SD
Demo
Ying
Y
Fang
Mark N
MN
Ho
Jing
J
Jiang
Christopher J
CJ
Kirk
Guy J
GJ
Laidig
Evan R
ER
Lewis
Yan
Y
Lu
Tony
T
Muchamuel
Francesco
F
Parlati
Eileen
E
Ring
Kevin D
KD
Shenk
Jamie
J
Shields
Peter J
PJ
Shwonek
Timothy
T
Stanton
Congcong M
CM
Sun
Catherine
C
Sylvain
Tina M
TM
Woo
Jinfu
J
Yang
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
C540947:3-methoxy-2-(3-methoxy-2-((2-methyl-1,3-thiazol-5-yl)formamido)propanamido)-N-(1-(2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide; D000970:Antineoplastic Agents; D004151:Dipeptides; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D013844:Thiazoles; C524865:carfilzomib