The small organic molecule C19 binds and strengthens the KRAS4b-PDEδ complex and inhibits growth of colorectal cancer cells in vitro and in vivo.

ABSTRACT:

Background

Colorectal cancer is the third most common cancer worldwide; and in 40% of all cases, KRAS4b-activating mutations occur. KRAS4b is transported by phosphodiesterase-6δ (PDEδ) to the plasma membrane, where it gets activated. PDEδ downregulation prevents redistribution and activation of KRAS4b. Thus, targeting the KRAS4b-PDEδ complex is a treatment strategy for colorectal cancer.

Methods

Using docking and molecular dynamics simulations coupled to molecular mechanics, the generalized born model and solvent accessibility (MMGBSA) approach to explore protein-ligand stability, we found that the compound ((2S)-N-(2,5-diclorofenil)-2-[(3,4-dimetoxifenil)metilamino]-propanamida), termed C19, bound and stabilized the KRAS4b-PDEδ complex. We investigated whether C19 decreases

SUBMITTER: Cruz-Nova P 

PROVIDER: S-EPMC6211466 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature