10.1021/acsmedchemlett.7b00164.s001
Zhenhua Huang
Zhenhua
Huang
Heran Li
Heran
Li
Qian Zhang
Qian
Zhang
Fangzheng Lu
Fangzheng
Lu
Mei Hong
Mei
Hong
Zhigang Zhang
Zhigang
Zhang
Xiaocui Guo
Xiaocui
Guo
Yuanju Zhu
Yuanju
Zhu
Sanming Li
Sanming
Li
Hongzhuo Liu
Hongzhuo
Liu
Discovery of Indolinone-Based Multikinase Inhibitors
as Potential Therapeutics for Idiopathic Pulmonary Fibrosis
American Chemical Society
2017
c-KIT
Indolinone-Based Multikinase Inhibitors
novel multikinase inhibitor
IPF
28- day survival rate
antifibrosis agent nintedanib
PK
KBP -7018
BLM
RET
Idiopathic Pulmonary Fibrosis Idiopathic
tyrosine kinase-selective inhibitor
PDGFR
report novel indolinone-based multikinase inhibitors
2017-09-30 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Discovery_of_Indolinone-Based_Multikinase_Inhibitors_as_Potential_Therapeutics_for_Idiopathic_Pulmonary_Fibrosis/5484745
Idiopathic pulmonary fibrosis (IPF)
is a serious and deadly disease
for which treatment options are limited. The recent approval of antifibrosis
agent nintedanib represents one of the first therapeutic approaches
for the treatment of IPF. Here, we report novel indolinone-based multikinase
inhibitors that target angiogenesis and fibrosis pathways and may
serve as potential therapeutics for IPF. KBP-7018 is a novel, tyrosine
kinase-selective inhibitor with potent effects on three fibrotic kinases
(c-KIT, PDGFR, and RET). The pharmacokinetics (PK) properties of KBP-7018
were favorable in mice, rats, and dogs. In a bleomycin (BLM)-induced
mouse pulmonary fibrosis model, 10, 30, and 100 mg/kg daily doses
(q.d.) of KBP-7018 improved the 28-day survival rate in a dose-dependent
manner. The improved efficacy of KBP-7018 compared to nintedanib provided
a certain level of chemical validation for the involvement of PDGFR,
c-KIT, and RET in IPF. Thus, KBP-7018 represents a novel multikinase
inhibitor with differentiated activity, highly enhanced selectivity,
and acceptable PK profiles that will enter phase I clinical trials.