2. Academic Validation
  3. MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology

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

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.

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