| Literature DB >> 30034615 |
Sobhana Babu Boga1, Yongqi Deng2, Liang Zhu2, Yang Nan2, Alan B Cooper1, Gerald W Shipps2, Ronald Doll1, Neng-Yang Shih1, Hugh Zhu1, Robert Sun1, Tong Wang2, Sunil Paliwal1, Hon-Chung Tsui1, Xiaolei Gao1, Xin Yao1, Jagdish Desai1, James Wang1, Abdul Basit Alhassan1, Joseph Kelly1, Mehul Patel2, Kiran Muppalla2, Subrahmanyam Gudipati1, Li-Kang Zhang1, Alexei Buevich1, David Hesk1, Donna Carr1, Priya Dayananth1, Stuart Black1, Hong Mei1, Kathleen Cox1, Bradley Sherborne1, Alan W Hruza1, Li Xiao1, Weihong Jin1, Brian Long1, Gongjie Liu1, Stacey A Taylor1, Paul Kirschmeier1, William T Windsor1, Robert Bishop1, Ahmed A Samatar1.
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.Entities:
Year: 2018 PMID： 30034615 PMCID： PMC6047169 DOI： 10.1021/acsmedchemlett.8b00220
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345