Circle has developed a new paradigm for macrocycle drug discovery, combining structure-based rational design and advanced synthetic chemistry. Our platform facilitates the design and synthesis of intrinsically cell-permeable macrocycles that can address both intra- and extra-cellular therapeutic targets, and can be delivered by multiple routes, including oral administration. While the platform can be applied to challenging targets across a wide range of serious diseases, our pipeline is focused on developing macrocycles against intracellular protein-protein interactions that are key drivers in cancer.
Our lead programs target cyclin proteins, including cyclins A and E, which are part of the regulatory machinery that controls progression of cells through the cell cycle. Inhibition of cyclin A has been reported to be synthetic lethal to cancer cells that carry mutations causing dysregulation of the Retinoblastoma (Rb) pathway; we are researching the potential of macrocycles that inhibit cyclin A in a broad range of cancer types including small cell lung cancer (SCLC) where mutations in the Rb gene occur at a high frequency. Cyclin E is upregulated in many tumor types including uterine and ovarian cancer and is often associated with resistance to widely used cancer therapies, including trastuzumab and cdk4/6 inhibitors. Cyclin E is also implicated in diseases beyond cancer.