Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer.
The proteasome was validated as an oncology target following the clinical success of VELCADE (bortezomib) for injection for the treatment of multiple myeloma and recurring mantle cell lymphoma. Consequently, several groups are pursuing the development of additional small-molecule proteasome inhibitors for both hematologic and solid tumor indications. Here, we describe MLN9708, a selective, orally bioavailable, second-generation proteasome inhibitor that is in phase I clinical development. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib. MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirmed that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 showed activity in both solid tumor and hematologic preclinical xenograft models, and we found a correlation between greater pharmacodynamic responses and improved antitumor activity. Moreover, antitumor activity was shown via multiple dosing routes, including oral gavage. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications.
Kupperman
Erik
E
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. erik.kupperman@mpi.com
Lee
Edmund C
EC
Cao
Yueying
Y
Bannerman
Bret
B
Fitzgerald
Michael
M
Berger
Allison
A
Yu
Jie
J
Yang
Yu
Y
Hales
Paul
P
Bruzzese
Frank
F
Liu
Jane
J
Blank
Jonathan
J
Garcia
Khristofer
K
Tsu
Christopher
C
Dick
Larry
L
Fleming
Paul
P
Yu
Li
L
Manfredi
Mark
M
Rolfe
Mark
M
Bolen
Joe
J
D000818:Animals; D001896:Boron Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D015853:Cysteine Proteinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000097:blood; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D001896:Boron Compounds; D001897:Boronic Acids; D015853:Cysteine Proteinase Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; C548400:ixazomib; D046988:Proteasome Endopeptidase Complex; D005998:Glycine