MK-8353: Discovery of an Orally Bioavailable DualMechanism ERK Inhibitor for Oncology

摘要

The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, a novel series of pyrrolidine derivatives (compound >5) were identified as potent inhibitors of ERK1/2 with excellent kinase selectivity and dual mechanism of action but suffered from poor pharmacokinetics (PK). The challenge of PK was overcome by the discovery of a novel 3(S)-thiomethyl pyrrolidine analog >7. Lead optimization through focused structure–activity relationship led to the discovery of a clinical candidate >MK-8353 suitable for twice daily oral dosing as a potential new cancer therapeutic.