Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors.

ABSTRACT: The success of acrylamide-containing drugs in treating cancers has spurred a passion to search for acrylamide bioisosteres. In our endeavour, we have identified that an allenamide group can be a reactive bioisostere of the acrylamide group. In our development of allenamide-containing compounds, we found that the most potent compound, 14, inhibited the kinase activities of both T790M/L858R double mutant and wild type EGFR in a low nM range. 14 also inhibited the growth of NCI-H1975 lung cancer cells at IC₅₀ = 33 nM, which is comparable to that of acrylamide-containing osimertinib. The western blot analysis showed that the phosphorylation of EGFR, AKT, and ERK1/2 was simultaneously inhibited in a dose-dependent manner when NCI-H1975 cells were treated with 14.

SUBMITTER: Chen D 

PROVIDER: S-EPMC6083791 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature