135065-69-9Relevant articles and documents
HPK1 ANTAGONISTS AND USES THEREOF
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Paragraph 0836; 0837, (2021/03/19)
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of HPK1, and the treatment of HPK1-mediated disorders.
Development of the First Generation of Disulfide-Based Subtype-Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) Inhibitors
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)
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.
Synthesis of reboxetine intermediate and carnitine acetyltransferase inhibitor via NBS-induced electrophilic multicomponent reaction
Zhou, Jing,Yeung, Ying-Yeung
, p. 4644 - 4649 (2014/06/09)
N-Bromosuccinimide-induced electrophilic multicomponent reaction has been applied to the synthesis of Reboxetine intermediate, a highly potent selective norepinephrine reuptake inhibitor. By simply changing the olefinic partner, the synthesis of a carniti
