Novel Small Molecules Disabling the IL-6/IL-6R/GP130 Heterohexamer Complex

摘要

There is an inherent connection between cancer and chronic inflammation. One of the key inflammatory cytokines, IL-6, is a strong biomarker and therapeutic target of breast tumor progression, especially for late-stage, metastatic and resistant breast cancers. This project is to develop first-in-class small molecule IL-6 inhibitors for potential novel drug discovery. We focus on small molecule design disrupting IL-6/GP130 D1 domain since a) this is the weakest protein-protein binding interface in the IL-6/IL- 6R/GP130 signaling hexameric complex; b) D1 domain is not required for OSM and LIF cytokines, thus achieving design feasibility and reducing side-effects. Through structure-based computational design, combined with synthetic medicinal chemistry and cancer cell biology efforts, we have discovered two major classes of small molecule IL-6 inhibitors: a) MDL-5/MDL-16. We built model of natural compound MDL-A binding to GP130 D1 domain; re-engineered pentendione ring into hydroxybenzene to ease synthetic challenge and added carboxybenzyl ring to gain 10-fold extra binding potency. b) Evista (Raloxifene) and Viviant (Bazedoxifene). We used computational drug repositioning strategy to discover that FDA-approved antiosteoporosis drugs Evista (Raloxifene) and Viviant (Bazedoxifene) are IL-6/GP130 D1 domain inhibitors. These compounds were proved to molecularly bind to GP130 D1 domain as designed and showed significant effects in IL-6/STAT3 signaling inhibition and breast cancer cellular apoptosis, thus are novel lead molecules to be modified and tested further to become novel anti-metastasis and anti-resistance breast cancer drugs.