Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors.
The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization and developed a series of 13-membered macrocycles. The structure-activity relationships of the macrocyclic linker were systematically explored, leading to the identification of 9c as a potent, subnanomolar inhibitor of Pim-1 and -2. This molecule also potently inhibited Pim kinase activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2, both in vitro (pBAD IC50 = 25 nM) and in vivo (pBAD EC50 = 30 nM, unbound), and a 100 mg/kg daily dose was found to completely arrest the growth of KMS-12-BM xenografts in mice.
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Victor J
VJ
Cee
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Frank
F
Chavez
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Bradley
B
Herberich
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Brian A
BA
Lanman
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Liping H
LH
Pettus
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Anthony B
AB
Reed
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Bin
B
Wu
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Ryan P
RP
Wurz
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Kristin L
KL
Andrews
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Jie
J
Chen
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Dean
D
Hickman
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Jimmy
J
Laszlo
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Matthew R
MR
Lee
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Nadia
N
Guerrero
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Bethany K
BK
Mattson
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Yen
Y
Nguyen
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Christopher
C
Mohr
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Karen
K
Rex
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Christine E
CE
Sastri
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Paul
P
Wang
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Qiong
Q
Wu
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Tian
T
Wu
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Yang
Y
Xu
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Yihong
Y
Zhou
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Jeffrey T
JT
Winston
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
J Russell
JR
Lipford
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Andrew S
AS
Tasker
Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Hui-Ling
HL
Wang
KMS-12-BM; Pim kinase inhibitor; macrocycle; multiple myeloma