Design and biological characterization of a series of dual mechanism ERK1/2 inhibitors with a Triazolopyridinone core

Sajedeh Lotfaliansaremi, Stephen Cornwell, Candice Casillas, Michael Sabio, Peter Tolias, William Windsor, Sunil Paliwal

Research output: Contribution to journalArticlepeer-review

Abstract

Oncology clinical development programs have targeted the RAS/RAF/MEK/ERK signaling pathway with small molecule inhibitors for a variety of cancers during the past decades, and most therapies have shown limited or minimal success. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, most cancers have shown treatment resistance after several months of inhibitor usage, and reports indicate resistance is often associated with the reactivation of the MAPK signaling pathway. It is widely accepted that an effective MAPK therapy will have a significant impact on curtailing cancer growth and improving patient survival. However, despite more than three decades of intense research and pharmaceutical industry efforts, an FDA-approved, effective anti-cancer ERK inhibitor has yet to be developed. Here, we present the design, optimization, and biological characterization of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate the phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. Our series of dual mechanism ERK1/2 inhibitors, in which we incorporated a triazolopyridinone core, may present potential benefits for enhancing efficacy and addressing the emergence of treatment resistance.

Original languageEnglish
Pages (from-to)837-847
Number of pages11
JournalChemical Biology and Drug Design
Volume101
Issue number4
DOIs
StatePublished - Apr 2023

Keywords

  • cancer
  • clinical trials
  • computational chemistry
  • extracellular signal-regulated kinase inhibitors
  • mitogen-activated protein kinase
  • structure-based drug design
  • triazolopyridinone

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