1346540-97-3Relevant academic research and scientific papers
Design and synthesis of novel substituted naphthyridines as potential c-Met kinase inhibitors based on MK-2461
Wu, Jing-Fang,Liu, Ming-Ming,Huang, Shao-Xu,Wang, Yang
, p. 3251 - 3255 (2015)
Abstract Two series of novel 1,5-naphthyridine and 1,6-naphthyridine derivatives were designed and synthesized based on the c-Met kinase inhibitor MK-2461 under the guidance of scaffold hopping strategy. All were tested on c-Met kinase and in vitro anti-tumor activities against Hela and A549 cell lines. The results indicated that 1,6-naphthyridine was a more promising c-Met inhibitory structure core compared with 1,5-naphthyridine. Among them, 26b and 26c showed the best enzymic and cytotoxic activities. The western blot experiments implied that the cytotoxic activity of 26c might be partially through suppressing the phosphorylation of c-Met kinase.
Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRASG12C
Bader, Benjamin,Badock, Volker,Bauser, Marcus,Briem, Hans,Christ, Clara D.,Eis, Knut,Friberg, Anders,Gradl, Stefan,Hillig, Roman C.,Moosmayer, Dieter,Mortier, Jérémie,Nguyen, Duy,Schroeder, Jens,Siegel, Franziska,Steigemann, Patrick
supporting information, (2020/04/17)
Due to its frequent mutations in multiple lethal cancers, KRAS is one of the most-studied anticancer targets nowadays. Since the discovery of the druggable allosteric binding site containing a G12C mutation, KRASG12C has been the focus of attention in oncology research. We report here a computationally driven approach aimed at identifying novel and selective KRASG12C covalent inhibitors. The workflow involved initial enumeration of virtual molecules tailored for the KRAS allosteric binding site. Tools such as pharmacophore modeling, docking, and free-energy perturbations were deployed to prioritize the compounds with the best profiles. The synthesized naphthyridinone scaffold showed the ability to react with G12C and inhibit KRASG12C. Analogues were prepared to establish structure-activity relationships, while molecular dynamics simulations and crystallization of the inhibitor-KRASG12C complex highlighted an unprecedented binding mode.
IDENTIFICATION AND USE OF KRAS INHIBITORS
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Page/Page column 45, (2020/12/07)
The present invention relates to compounds of formula (1) in which A, U and R1 are as defined herein, to pharmaceutical compositions and combinations comprising the compounds according to the invention, and to the prophylactic and therapeutic use of the inventive compounds, respectively to the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for neoplastic disorders, repectively cancer or conditions with dysregulated immune responses or other disorders associated with aberrant KRAS signaling, as a sole agent or in combination with other active ingredients.
