1. MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology.
- Author
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Boga SB, Deng Y, Zhu L, Nan Y, Cooper AB, Shipps GW Jr, Doll R, Shih NY, Zhu H, Sun R, Wang T, Paliwal S, Tsui HC, Gao X, Yao X, Desai J, Wang J, Alhassan AB, Kelly J, Patel M, Muppalla K, Gudipati S, Zhang LK, Buevich A, Hesk D, Carr D, Dayananth P, Black S, Mei H, Cox K, Sherborne B, Hruza AW, Xiao L, Jin W, Long B, Liu G, Taylor SA, Kirschmeier P, Windsor WT, Bishop R, and Samatar AA
- 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 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., Competing Interests: The authors declare no competing financial interest.
- Published
- 2018
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