259860-00-9Relevant articles and documents
HETEROCYCLIC COMPOUNDS, PREPARATION METHODS AND USES THEREOF
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Paragraph 194; 196, (2020/12/07)
Provided herein are novel compounds, for example, compounds having a Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. Also provided herein are methods of preparing the compounds and methods of using the compounds, for example, in inhibiting KRAS G12C in a cell, and/or in treating various cancer such as pancreatic cancer, endometrial cancer, colorectal cancer, or lung cancer (e.g., non-small cell lung cancer).
Design, Synthesis, and Biological Evaluation of Novel Type I1/2 p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine
Walter, Niklas M.,Wentsch, Heike K.,Bührmann, Mike,Bauer, Silke M.,D?ring, Eva,Mayer-Wrangowski, Svenja,Sievers-Engler, Adrian,Willemsen-Seegers, Nicole,Zaman, Guido,Buijsman, Rogier,L?mmerhofer, Michael,Rauh, Daniel,Laufer, Stefan A.
supporting information, p. 8027 - 8054 (2017/10/18)
We recently reported 1a (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase's R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I1/2 binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives.
From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl)maleimides as glycogen synthase kinase 3βinhibitors that suppress proliferation and survival of pancreatic cancer cells
Gaisina, Irina N.,Gallier, Franck,Ougolkov, Andrei V.,Kim, Ki H.,Kurome, Toru,Guo, Songpo,Holzle, Denise,Luchini, Doris N.,Blond, Sylvie Y.,Billadeau, Daniel D.,Kozikowski, Alan P.
supporting information; experimental part, p. 1853 - 1863 (2009/12/31)
Recent studies have demonstrated that glycogen synthase kinase 3β (GSK-3β) is overexpressed in human colon and pancreatic carcinomas, contributing to cancer cell proliferation and survival. Here, we report the design, synthesis, and biological evaluation of benzofuran-3-yl-(indol-3-yl) maleimides, potent GSK-3β inhibitors. Some of these compounds show picomolar inhibitory activity toward GSK-3β and an enhanced selectivity against cyclin-dependent kinase 2 (CDK-2). Selected GSK-3β inhibitors were tested in the pancreatic cancer cell lines MiaPaCa-2, BXPC-3, and HupT3. We determined that some of these compounds, namely compounds 5, 6, 11, 20, and 26, demonstrate antiproliferative activity against some or all of the pancreatic cancer cells at low micromolar to nanomolar concentrations. We found that the treatment of pancreatic cancer cells with GSK-3β inhibitors 5 and 26 resulted in suppression of GSK-3β activity and a distinct decrease of the X-linked inhibitor of apoptosis (XIAP) expression, leading to significant apoptosis. The present data suggest a possible role for GSK-3β inhibitors in cancer therapy, in addition to their more prominent applications in CNS disorders.
