A first-in-class selective inhibitor of ERK1/2 and ERK5 overcomes drug resistance with a single-molecule strategy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Acquired drug resistance to kinase-targeted therapies, including KRAS and MEK inhibitors, remains a significant clinical challenge.
• Extracellular-regulated kinase 1/2 (ERK1/2) is a conserved target at the pathway terminus, but monotherapy has limited success due to resistance.
• Extracellular-regulated kinase 5 (ERK5) acts as a compensatory pathway upon ERK1/2 inhibition, particularly in triple-negative breast cancer (TNBC).

Purpose of the Study:

• To develop a novel therapeutic strategy targeting both ERK1/2 and ERK5 to overcome drug resistance in TNBC.
• To computationally design and characterize a first-in-class polypharmacology molecule targeting ERK1/2 and ERK5.

Main Methods:

• Computational design of a dual-targeting molecule, SKLB-D18, utilizing polypharmacology principles.
• In vitro and in vivo evaluation of SKLB-D18's potency, specificity, tolerability, and anti-tumor efficacy in preclinical models.
• Mechanistic studies investigating SKLB-D18's role in autophagy, mTOR/p70S6K, NCOA4-mediated ferroptosis, and multidrug resistance mitigation.

Main Results:

• SKLB-D18 selectively targets ERK1/2 and ERK5 with nanomolar potency and high specificity.
• SKLB-D18 demonstrated excellent tolerability in mice.
• SKLB-D18 exhibited superior in vivo anti-tumor efficacy compared to the clinical ERK1/2 inhibitor BVD-523 and a combination regimen of BVD-523 and an ERK5 inhibitor.

Conclusions:

• ERK5 acts as a compensatory pathway following ERK1/2 inhibition in TNBC.
• SKLB-D18, a dual ERK1/2 and ERK5 inhibitor, represents a promising therapeutic candidate for TNBC.
• SKLB-D18's mechanism involving autophagy and ferroptosis may overcome multidrug resistance.