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

Sobhana Babu Boga, Yongqi Deng, Liang Zhu, Yang Nan, Alan B. Cooper, Gerald W. Shipps, Ronald Doll, Neng Yang Shih, Hugh Zhu, Robert Sun, Tong Wang, Sunil Paliwal, Hon Chung Tsui, Xiaolei Gao, Xin Yao, Jagdish Desai, James Wang, Abdul Basit Alhassan, Joseph Kelly, Mehul PatelKiran Muppalla, Subrahmanyam Gudipati, Li Kang Zhang, Alexei Buevich, David Hesk, Donna Carr, Priya Dayananth, Stuart Black, Hong Mei, Kathleen Cox, Bradley Sherborne, Alan W. Hruza, Li Xiao, Weihong Jin, Brian Long, Gongjie Liu, Stacey A. Taylor, Paul Kirschmeier, William T. Windsor, Robert Bishop, Ahmed A. Samatar

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish
Pages (from-to)761-767
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume9
Issue number7
DOIs
StatePublished - 12 Jul 2018

Keywords

  • ERK inhibitor
  • MAPK pathway
  • MK-8353
  • kinase selectivity
  • lead optimization
  • oncology

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