- Development of the First Generation of Disulfide-Based Subtype-Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors
-
Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metabolism. We previously described bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, on the basis of the scaffold of 16, we identify two novel types of disulfide-based PDK1 inhibitors. The most potent analogue, 3a, effectively inhibits PDK1 both at the molecular (kinact/Ki = 4.17 × 103 M-1 s-1) and the cellular level (down to 0.1 μM). In contrast to 16, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4. 3a also significantly alters glucose metabolic pathways in A549 cells by decreasing ECAR and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no negative effect to the mice weight. Collectively, these data demonstrate that 3a may be an excellent lead compound for the treatment of cancer as a first-generation subtype-selective and covalent PDK1 inhibitor.
- Liu, Yifu,Xie, Zuoquan,Zhao, Dan,Zhu, Jin,Mao, Fei,Tang, Shuai,Xu, Hui,Luo, Cheng,Geng, Meiyu,Huang, Min,Li, Jian
-
p. 2227 - 2244
(2017/04/03)
-
- N-ACYL CYCLIC AMINE DERIVATIVE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
-
The present invention provides compounds which show high effectiveness against positive symptoms, negative symptoms and cognitive dysfunction in schizophrenia and reduce conventional side-effect risks as well as have remarkable effects for central neurolo
- -
-
-
- NEW AZETIDINE DERIVATIVES AS NEUROKININ RECEPTOR ANTAGONISTS FOR THE TREATMENT OF GASTROINTESTINAL DISEASES
-
The application relates to new piperazine- or morpholine-substituted azetidine derivatives of formula I. These compounds are antagonists at the neurokinin receptor and can be used for the treatment of gastrointestinal diseases. The application also relate
- -
-
Page/Page column 32
(2008/06/13)
-
- NEW AZETIDINE DERIVATIVES AS NEUROKININ RECEPTOR ANTAGONISTS FOR THE TREATMENT OF GASTROINTESTINAL DISEASES
-
The present invention relates to new azetidine derivatives of formula I, to pharmaceutical compositions containing said compounds and to the use of said compounds as neurokinin (NK) receptor antagonists in the treatment of gastrointestinal diseases. The invention further relates to processes for the preparation of compounds of formula I and to new intermediates used in the preparation thereof .
- -
-
Page/Page column 43
(2010/11/25)
-