An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer.
The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.
Soucy
Teresa A
TA
Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA. teresa.soucy@mpi.com
Smith
Peter G
PG
Milhollen
Michael A
MA
Berger
Allison J
AJ
Gavin
James M
JM
Adhikari
Sharmila
S
Brownell
James E
JE
Burke
Kristine E
KE
Cardin
David P
DP
Critchley
Stephen
S
Cullis
Courtney A
CA
Doucette
Amanda
A
Garnsey
James J
JJ
Gaulin
Jeffrey L
JL
Gershman
Rachel E
RE
Lublinsky
Anna R
AR
McDonald
Alice
A
Mizutani
Hirotake
H
Narayanan
Usha
U
Olhava
Edward J
EJ
Peluso
Stephane
S
Rezaei
Mansoureh
M
Sintchak
Michael D
MD
Talreja
Tina
T
Thomas
Michael P
MP
Traore
Tary
T
Vyskocil
Stepan
S
Weatherhead
Gabriel S
GS
Yu
Jie
J
Zhang
Julie
J
Dick
Lawrence R
LR
Claiborne
Christopher F
CF
Rolfe
Mark
M
Bolen
Joseph B
JB
Langston
Steven P
SP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D000075687:NEDD8 Protein; D009369:Neoplasms / Q000188:drug therapy*; D061988:Proteasome Inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
D000970:Antineoplastic Agents; D044842:Cullin Proteins; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C513172:Nedd8 protein, mouse; D061988:Proteasome Inhibitors; D011743:Pyrimidines; D014452:Ubiquitins; D044764:Ubiquitin-Activating Enzymes; C539933:pevonedistat