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

Abstract

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 <b>5</b>) 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(<i>S</i>)-thiomethyl pyrrolidine analog <b>7</b>. Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate <b>MK-8353</b> suitable for twice daily oral dosing as a potential new cancer therapeutic.