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 ) 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()-thiomethyl pyrrolidine analog . Lead optimization through focused structure-activity relationship led to the discovery of a clinical candidate suitable for twice daily oral dosing as a potential new cancer therapeutic.
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| http://dx.doi.org/10.1021/acsmedchemlett.8b00220 | DOI Listing |
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