The primary research goals of the Fletcher Laboratory are the modulation of aberrant alpha-helix-mediated protein-protein and protein-DNA interactions via novel, small molecule-based recognition strategies in order to develop new therapeutics to treat human diseases, including cancer, diabetes and a unique strategy to tackle Alzheimer’s.
Bcl-xL and Mcl-1 Inhibitors
A hallmark of cancer is dysregulation of apoptosis (programmed cell death). Bcl-xL and Mcl-1 are anti-apoptotic members of the Bcl-2 family of proteins. The anti-apoptotic function of Bcl-xL and Mcl-1 is neutralized by the helical BH3 domain of pro-apoptotic Bcl-2 proteins, such as Bim and Bak. In normal cells, the expression of anti- and pro-apoptotic cells is tightly regulated to ensure the correct balance of cell survival and cell death. Bcl-xL and Mcl-1 are over-expressed in a variety of human cancers, including lung, breast, pancreatic and colon cancers. Small-molecules that can effectively emulate the helical BH3 domain of Bim and Bak have been shown to inhibit the anti-apoptotic function of Bcl-xL and Mcl-1. Whilst potent Bcl-xL inhibitors, such as ABT-737, have been identified, the likewise inhibition of Mcl-1 remains elusive. In a two-pronged approach, we have developed potent inhibitors of Mcl-1 through (b) the development of synthetic mimetics of the BH3 alpha-helices, and (b) structure-based design via analysis of the BH3-binding crevice on the surface of Mcl-1.
c-Myc is a transcription factor whose functions include the regulation of apoptosis, proliferation and differentation. The pharmacologic inhibition of c-Myc has resulted in the inhibition of tumor growth with minimal toxicity to healthy cells, suggesting the inhibition of c-Myc is a potentially powerful strategy towards enhancing the armory of anti-cancer drugs. In its monomeric form, c-Myc is inactive, becoming transcriptionally functional only upon its heterodimerization with Max to afford a coiled coil that can recognize the E-box sequence 5′-CACGTG-3′ (right). However, as an intrinsically disordered protein, the rational design of c-Myc inhibitors is particularly challenging. Nevertheless, a high throughput screen has afforded several small-molecules that bind c-Myc and inhibit its dimerization – we are currently in the process of optimizing these hit compounds. In a complementary approach, we have designed synthetic alpha-helix mimetics to perturb the helix-helix interface of the c-Myc-Max dimer as a novel means of c-Myc inhibition through perturbation of the dimer that compromises its DNA binding ability.