Protein-protein interactions (PPIs) are fundamental biochemical processes that regulate numerous cellular pathways, and often found to be mediated by key secondary structures like a-helices. Whereas short peptides derived from proteins have been used to inhibit such PPIs, peptides in general may suffer from drawbacks that severely compromise their effective in vivo use, such as rapid degradation, poor bioavailability, and low cell permeability. Thus, small molecules that mimic functions of helical peptides would be of great interest in targeting and disrupting PPIs that take place inside cells.
We have designed oligo-benzamides as rigid templates to emulate protein helical surfaces. A tris-benazmide scaffold can place 3 functional groups to match the side chains found at the i, i+4, and i+7 positions in a helix. And, it can accommodate two additional functional groups at its N- and C-termini to render higher target interaction/selectivity and improved physicochemical properties. In addition, tris-benzamides are easy to be assembled by following high-yielding and iterative steps in solution- and solid-phase.
As estrogen receptor (ER) recognizes a helical and consensus LXXLL motif to recruit its coregulators, we have designed and synthesized a series of tris-benzamides based structural design. A leading compound TK11 disrupts both ER dimerization and interaction with several coregulators, and effectively blocks ER-mediated oncogenic signaling. It showed potent growth inhibition on therapy-sensitive and -resistant breast cancer cells, in both preclinical mouse xenograft models and patient-derived tumor explant models. It is orally bioavailable with no identifiable toxicity, showing a new mechanism of action to treat breast cancer.