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

  • ACS Med Chem Lett. 2018 Jun 14;9(7):761-767. doi: 10.1021/acsmedchemlett.8b00220.
Sobhana Babu Boga  1 ,  Yongqi Deng  2 ,  Liang Zhu  2 ,  Yang Nan  2 ,  Alan B Cooper  1 ,  Gerald W Shipps Jr  2 ,  Ronald Doll  1 ,  Neng-Yang Shih  1 ,  Hugh Zhu  1 ,  Robert Sun  1 ,  Tong Wang  2 ,  Sunil Paliwal  1 ,  Hon-Chung Tsui  1 ,  Xiaolei Gao  1 ,  Xin Yao  1 ,  Jagdish Desai  1 ,  James Wang  1 ,  Abdul Basit Alhassan  1 ,  Joseph Kelly  1 ,  Mehul Patel  2 ,  Kiran Muppalla  2 ,  Subrahmanyam Gudipati  1 ,  Li-Kang Zhang  1 ,  Alexei Buevich  1 ,  David Hesk  1 ,  Donna Carr  1 ,  Priya Dayananth  1 ,  Stuart Black  1 ,  Hong Mei  1 ,  Kathleen Cox  1 ,  Bradley Sherborne  1 ,  Alan W Hruza  1 ,  Li Xiao  1 ,  Weihong Jin  1 ,  Brian Long  1 ,  Gongjie Liu  1 ,  Stacey A Taylor  1 ,  Paul Kirschmeier  1 ,  William T Windsor  1 ,  Robert Bishop  1 ,  Ahmed A Samatar  1
Affiliations
  • 1. Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
  • 2. Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
PMID: 30034615 DOI: 10.1021/acsmedchemlett.8b00220
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.