Discovery of 5,6-Bis(4-methoxy-3-methylphenyl)pyridin-2-amine as a WSB1 Degrader to Inhibit Cancer Cell Metastasis

Abstract

The gain of cell motility is an essential prerequisite for cancer metastasis. The ubiquitin ligase subunit WD repeat and SOCS box-containing 1 (WSB1) has been demonstrated to regulate hypoxia-driven tumor cell migration. However, there is still a lack of methods for discovering inhibitors targeting the WSB1 axis. Here, we employed phenotypic screening models and identified compound 4 that displayed migration inhibitory activity against WSB1-overexpressing cells. Further studies indicated that it may function as a WSB1 degrader, thus leading to the accumulation of the Rho guanosine diphosphate dissociation inhibitor 2 (RhoGDI2) protein, reversing the expression of downstream F-actin and formation of membrane ruffles, and disturbing the migration capacity of cancer cells. Moreover, compound 4 exhibited a promising in vivo anticancer metastatic effects. Our findings show the discovery of a new WSB1 degrader, providing a unique solution for the treatment of cancer metastasis.

Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer

“…Considering that the lysosomal pathway can also cause protein degradation, chloroquine (a lysosomal inhibitor) was utilized to investigate the effect of the ANXA3 degradation by ( R )-SL18. It was found that chloroquine (20 μmol/L, 5 h) 34 had little effect on the protein level of ANXA3 by treatment with ( R )-SL18 ( Fig. S7E ).…”

The Dual Function of RhoGDI2 in Immunity and Cancer

“…WSB1 was also shown to drive the metastatic potential of OS in vitro and in the BALB/c (nu/nu) mouse model. Of most interest in this context is that RhoGDI2 overexpression in OS cells and mice is able to reverse the spreading of the WSB1-induced metastasis [ 50 , 51 ], demonstrating its direct participation in OS progression.…”

Identification of Potential WSB1 Inhibitors by AlphaFold Modeling, Virtual Screening, and Molecular Dynamics Simulation Studies

“…ere are many research studies about WSB1 regulating tumor progression [17][18][19][20][21]. WSB1 was found to drive the metastatic potential in osteosarcoma cells which correlated with the pulmonary metastatic potential.…”