53663-18-6Relevant articles and documents
Design of a "two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites
Wittlinger, Florian,Heppner, David E.,To, Ciric,Günther, Marcel,Shin, Bo Hee,Rana, Jaimin K.,Schmoker, Anna M.,Beyett, Tyler S.,Berger, Lena M.,Berger, Benedict-Tilman,Bauer, Nicolas,Vasta, James D.,Corona, Cesear R.,Robers, Matthew B.,Knapp, Stefan,J?nne, Pasi A.,Eck, Michael J.,Laufer, Stefan A.
supporting information, p. 1370 - 1383 (2021/11/13)
Inhibitors targeting the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harboring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations has motivated the development of successive generations of inhibitors that bind in the ATP site. The third-generation agent osimertinib is now a first-line treatment for this disease. Recently, allosteric inhibitors have been developed to overcome drug-resistant mutations that confer a resistance to osimertinib. Here, we present the structure-guided design and synthesis of a mutant-selective lead compound, which consists of a pyridinyl imidazole-fused benzylisoindolinedione scaffold that simultaneously occupies the orthosteric and allosteric sites. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with a significantly lower activity for wild-type EGFR (47 nM). Additionally, this compound achieves modest cetuximab-independent and mutant-selective cellular efficacies on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants.
Novel HDAC/tubulin dual inhibitor: Design, synthesis and docking studies of α-phthalimidochalcone hybrids as potential anticancer agents with apoptosis-inducing activity
Jones, Peter G.,Mourad, Ahmed A E.,Mourad, Mai A E.
, p. 3111 - 3130 (2020/08/07)
Introduction: In order to develop novel anticancer HDAC/tubulin dual inhibitors, a novel series of α-phthalimido-substituted chalcones-based hybrids was synthesized and characterized by IR,1H NMR,13C NMR, mass spectroscopy and X-ray analysis. Methods: All the synthesized compounds were evaluated for their in vitro anticancer activity against MCF-7 and HepG2 human cancer cell lines using MTT assay. To explore the mechanism of action of the synthesized compounds, in vitro β-tubulin polymerization and HDAC 1 and 2 inhibitory activity were measured for the most potent anticancer hybrids. Further, cell cycle analysis was also evaluated. Results: The trimethoxy derivative 7j showed the most potent anticancer activity, possessed the most potent β-tubulin polymerase and HDAC 1 and 2 inhibitory activity and efficiently induced cell cycle arrest at both G2/M and preG1phases in the MCF-7 cell line.
Traceless Directing Group Assisted Cobalt-Catalyzed C?H Carbonylation of Benzylamines
Ling, Fei,Ai, Chongren,Lv, Yaping,Zhong, Weihui
supporting information, p. 3707 - 3712 (2017/10/07)
The first example of cobalt-catalyzed C(sp2)?H carbonylation of benzylamines using a traceless directing group is reported, which was successfully applied to the synthesis of N?unprotected iso-indolinones through direct C?H/N?H bonds activation. This protocol tolerates a variety of functional groups and provides a facile and efficient method for the formal synthesis of (+)-garenoxacin. (Figure presented.).
