Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis.
Diverse biological roles for mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) have necessitated the identification of potent inhibitors in order to study its function in various disease contexts. In particular, compounds that can be used to carry out such studies in vivo would be critical for elucidating the potential for therapeutic intervention. A structure-based design effort coupled with property-guided optimization directed at minimizing the ability of the inhibitors to cross into the CNS led to an advanced compound 13 (GNE-495) that showed excellent potency and good PK and was used to demonstrate in vivo efficacy in a retinal angiogenesis model recapitulating effects that were observed in the inducible Map4k4 knockout mice.
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Chudi O
CO
Ndubaku
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Terry D
TD
Crawford
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Huifen
H
Chen
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Jason W
JW
Boggs
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Joy
J
Drobnick
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Seth F
SF
Harris
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Rajiv
R
Jesudason
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Erin
E
McNamara
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Jim
J
Nonomiya
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Amy
A
Sambrone
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Stephen
S
Schmidt
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Tanya
T
Smyczek
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Philip
P
Vitorino
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Lan
L
Wang
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Ping
P
Wu
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Stacey
S
Yeung
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Jinhua
J
Chen
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Kevin
K
Chen
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Charles Z
CZ
Ding
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Tao
T
Wang
Wuxi Apptec Co., Ltd. , 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, People's Republic of China.
Zijin
Z
Xu
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Stephen E
SE
Gould
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Lesley J
LJ
Murray
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Weilan
W
Ye
Angiogenesis; GNE-495; MAP4K4; P loop; naphthyridine