Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology

Sobhana Babu Boga, Abdul Basit Alhassan, Alan B. Cooper, Ronald Doll, Neng Yang Shih, Gerald Shipps, Yongqi Deng, Hugh Zhu, Yang Nan, Robert Sun, Liang Zhu, Jagdish Desai, Mehul Patel, Kiran Muppalla, Xiaolei Gao, James Wang, Xin Yao, Joseph Kelly, Subrahmanyam Gudipati, Sunil PaliwalHon Chung Tsui, Tong Wang, Bradley Sherborne, Li Xiao, Alan Hruza, Alexei Buevich, Li Kang Zhang, David Hesk, Ahmed A. Samatar, Donna Carr, Brian Long, Stuart Black, Priya Dayananth, William Windsor, Paul Kirschmeier, Robert Bishop

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 μM h; F% = 0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10 mpk = 26 μM h; F% = 70).

Original languageEnglish
Pages (from-to)2029-2034
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number11
DOIs
StatePublished - 15 Jun 2018

Keywords

  • ATP competitive
  • ERK inhibitor
  • Kinase selectivity
  • MAP kinases
  • Oncology

Fingerprint

Dive into the research topics of 'Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology'. Together they form a unique fingerprint.

Cite this