- Identification of Clinical Candidate M2698, a Dual p70S6K and Akt Inhibitor, for Treatment of PAM Pathway-Altered Cancers
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Herein, we report the discovery of a novel class of quinazoline carboxamides as dual p70S6k/Akt inhibitors for the treatment of tumors driven by alterations to the PI3K/Akt/mTOR (PAM) pathway. Through the screening of in-house proprietary kinase library, 4-benzylamino-quinazoline-8-carboxylic acid amide 1 stood out, with sub-micromolar p70S6k biochemical activity, as the starting point for a structurally enabled p70S6K/Akt dual inhibitor program that led to the discovery of M2698, a dual p70S6k/Akt inhibitor. M2698 is kinase selective, possesses favorable physical, chemical, and DMPK profiles, is orally available and well tolerated, and displayed tumor control in multiple in vivo studies of PAM pathway-driven tumors.
- Chen, Xiaoling,Clark, Anderson,Crowley, Lindsey,Deselm, Lizbeth,Georgi, Katrin,Goutopoulos, Andreas,Haxell, Thomas,Heasley, Brian H.,Huck, Bayard,Jackson, Jennifer,Johnson, Theresa,Jones, Reinaldo,Lan, Ruoxi,Lin, Jing,Machl, Andreas,Mochalkin, Igor,Moore, Joseph,Neagu, Constantin,Potnick, Justin,Richardson, Thomas E.,Rohdich, Felix,Sherer, Brian,Sutton, Amanda,Tian, Hui,Wilker, Erik,Xiao, Yufang
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supporting information
p. 14603 - 14619
(2021/10/20)
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- ROCK-INHIBITING COMPOUND AND USES THEREOF
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Disclosed herein are a compound of formula (I) and a preparation method and uses thereof. The compound shows a good inhibitory activity against ROCK, providing a new medicinal strategy to clinically treat the diseases associated with abnormal ROCK activity.
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Paragraph 0082; 0084-0086
(2020/05/07)
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- Pd(II)-Catalyzed Enantioselective C(sp3)-H Arylation of Free Carboxylic Acids
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A monoprotected aminoethyl amine chiral ligand based on an ethylenediamine backbone was developed to achieve Pd-catalyzed enantioselective C(sp3)-H arylation of cyclopropanecarboxylic and 2-aminoisobutyric acids without using exogenous directing groups. This new chiral catalyst affords new disconnection for preparing diverse chiral carboxylic acids from simple starting materials that are complementary to the various ring forming approaches.
- Shen, Peng-Xiang,Hu, Liang,Shao, Qian,Hong, Kai,Yu, Jin-Quan
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supporting information
p. 6545 - 6549
(2018/05/23)
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- A class of α-amino acids-derived multifunctional amidophosphane precatalysts: application to the highly enantio- and diastereoselective silver(I)-catalyzed 1,3-dipolar cycloaddition reaction
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A class of multifunctional amidophosphanes derived from chiral α-amino acids have been developed with two amide bonds, a tertiary amine and a phosphine. In combination with Ag(I) salts, these amidophosphanes have been demonstrated as highly efficient multifunctional catalysts in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides as well as the three-component reaction of the α-iminoesters in situ generated. Under optimal conditions, highly functionalized endo-8 pyrrolidines were obtained with good to excellent yields (up to 99% yield) and enantioselectivities (up to 98% ee).
- Hou, Yihui,Zhou, Zhipeng,Liu, Pingle,Wang, Jiankang,Hou, Qinglin,Wen, Pushan,Wang, Haifei
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p. 930 - 938
(2017/07/11)
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- Discovery of pyrroloaminopyrazoles as novel PAK inhibitors
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The P21-activated kinases (PAK) are emerging antitumor therapeutic targets. In this paper, we describe the discovery of potent PAK inhibitors guided by structure-based drug design. In addition, the efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo.
- Guo, Chuangxing,McAlpine, Indrawan,Zhang, Junhu,Knighton, Daniel D.,Kephart, Susan,Johnson, M. Catherine,Li, Haitao,Bouzida, Djamal,Yang, Anle,Dong, Liming,Marakovits, Joseph,Tikhe, Jayashree,Richardson, Paul,Guo, Lisa C.,Kania, Robert,Edwards, Martin P.,Kraynov, Eugenia,Christensen, James,Piraino, Joseph,Lee, Joseph,Dagostino, Eleanor,Del-Carmen, Christine,Deng, Ya-Li,Smeal, Tod,Murray, Brion W.
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p. 4728 - 4739
(2012/07/28)
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