Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR.
Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood-brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules were ultimately deemed not suitable for clinical development due to projected poor metabolic stability in humans. We, therefore, extended our studies to identify a BBB penetrating inhibitor of PI3K that was also projected to be metabolically stable in human. These efforts required identification of a distinct scaffold for PI3K inhibitors relative to our previous efforts and ultimately resulted in the identification of GDC-0084 (16). The discovery and preclinical characterization of this molecule are described within.
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Timothy P
TP
Heffron
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.
Laurent
L
Salphati
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Bruno
B
Alicke
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Jonathan
J
Cheong
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.
Kyle
K
Edgar
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.
Leslie B
LB
Lee
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
John D
JD
Lesnick
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Cristina
C
Lewis
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.
Jodie
J
Pang
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Emile G
EG
Plise
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Steve
S
Sideris
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Jeffrey
J
Wallin
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.
Xiaolin
X
Zhang
Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Alan G
AG
Olivero
CNS; PI3K; blood−brain barrier penetration; kinase inhibitor; oncology