TY - JOUR
T1 - Design and biological characterization of a series of dual mechanism ERK1/2 inhibitors with a Triazolopyridinone core
AU - Lotfaliansaremi, Sajedeh
AU - Cornwell, Stephen
AU - Casillas, Candice
AU - Sabio, Michael
AU - Tolias, Peter
AU - Windsor, William
AU - Paliwal, Sunil
N1 - Publisher Copyright:
© 2022 John Wiley & Sons Ltd.
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
KW - cancer
KW - clinical trials
KW - computational chemistry
KW - extracellular signal-regulated kinase inhibitors
KW - mitogen-activated protein kinase
KW - structure-based drug design
KW - triazolopyridinone
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U2 - 10.1111/cbdd.14186
DO - 10.1111/cbdd.14186
M3 - Article
C2 - 36434749
AN - SCOPUS:85144124647
SN - 1747-0277
VL - 101
SP - 837
EP - 847
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
IS - 4
ER -