Vertical pathway inhibition of receptor tyrosine kinases and BAD with synergistic efficacy in triple negative breast cancer.

ABSTRACT: Aberrant activation of the PI3K/AKT signaling axis along with the sustained phosphorylation of downstream BAD is associated with a poor outcome of TNBC. Herein, the phosphorylated to non-phosphorylated ratio of BAD, an effector of PI3K/AKT promoting cell survival, was observed to be correlated with worse clinicopathologic indicators of outcome, including higher grade, higher proliferative index and lymph node metastasis. The structural optimization of a previously reported inhibitor of BAD-Ser99 phosphorylation was therefore achieved to generate a small molecule inhibiting the phosphorylation of BAD at Ser99 with enhanced potency and improved oral bioavailability. The molecule 2-((4-(2,3-dichlorophenyl)piperazin-1-yl)(pyridin-3-yl)methyl) phenol (NCK) displayed no toxicity at supra-therape

SUBMITTER: Tan YQ 

PROVIDER: S-EPMC10781691 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature