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.
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. erik.kupperman@mpi.com
Erik
E
Kupperman
Edmund C
EC
Lee
Yueying
Y
Cao
Bret
B
Bannerman
Michael
M
Fitzgerald
Allison
A
Berger
Jie
J
Yu
Yu
Y
Yang
Paul
P
Hales
Frank
F
Bruzzese
Jane
J
Liu
Jonathan
J
Blank
Khristofer
K
Garcia
Christopher
C
Tsu
Larry
L
Dick
Paul
P
Fleming
Li
L
Yu
Mark
M
Manfredi
Mark
M
Rolfe
Joe
J
Bolen
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