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.
Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA. teresa.soucy@mpi.com
Teresa A
TA
Soucy
Peter G
PG
Smith
Michael A
MA
Milhollen
Allison J
AJ
Berger
James M
JM
Gavin
Sharmila
S
Adhikari
James E
JE
Brownell
Kristine E
KE
Burke
David P
DP
Cardin
Stephen
S
Critchley
Courtney A
CA
Cullis
Amanda
A
Doucette
James J
JJ
Garnsey
Jeffrey L
JL
Gaulin
Rachel E
RE
Gershman
Anna R
AR
Lublinsky
Alice
A
McDonald
Hirotake
H
Mizutani
Usha
U
Narayanan
Edward J
EJ
Olhava
Stephane
S
Peluso
Mansoureh
M
Rezaei
Michael D
MD
Sintchak
Tina
T
Talreja
Michael P
MP
Thomas
Tary
T
Traore
Stepan
S
Vyskocil
Gabriel S
GS
Weatherhead
Jie
J
Yu
Julie
J
Zhang
Lawrence R
LR
Dick
Christopher F
CF
Claiborne
Mark
M
Rolfe
Joseph B
JB
Bolen
Steven P
SP
Langston
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