Saturday, November 17, 2018

Balancing reactivity and antitumor activity: Heteroarylthio acetamide derivatives as potent and time-dependent inhibitors of EGFR

Riccardo Castelli, Nicole Bozza, Andrea Cavazzoni, Mara Bonelli, Federica Vacondio, Francesca Ferlenghi, Donatella Callegari, Claudia Silva, Silvia Rivara, Alessio Lodola, Graziana Digiacomo, Claudia Fumarola, Roberta Alfieri, Pier Giorgio Petronini, Marco Mor

European Journal of Medicinal Chemistry, 2018
DOI: 10.1016/j.ejmech.2018.11.029

Second- and third-generation inhibitors of EGFR possess an acrylamide group which alkylates Cys797, allowing to overcome resistance due to insurgence of T790M mutation. Less reactive warheads, yet capable to bind the target cysteine, may be useful to design newer and safer inhibitors. In the present work, we synthesized a 2-chloro-N-(4-(phenylamino)quinazolin-6-yl)acetamide (8) derivative as a prototype of EGFR inhibitor potentially able to react with Cys797 by nucleophilic substitution. We then tuned the reactivity of the acetamide fragment by replacing the chlorine leaving group with (hetero)-aromatic thiols or carboxylate esters. Among the synthesized derivatives, the 2-((1H-imidazol-2-yl)thio)acetamide 16, while showing negligible reactivity with cysteine in solution, caused long-lasting inhibition of wild-type EGFR autophosphorylation in A549 cells, resulted able to bind recombinant EGFR L858R/T790M in a time-dependent manner, and inhibited both EGFR autophosphorylation and proliferation in gefitinib-resistant H1975 (EGFR L858R/T790M) lung cancer cells at low micromolar concentration.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...