Discovery of potent, orally bioavailable ERK1/2 inhibitors with isoindolin-1-one structure by structure-based drug...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• The Mitogen-Activated Protein Kinase (MAPK) pathway, specifically the RAS/RAF/MEK/ERK cascade, is constitutively activated in numerous cancers, making it a key therapeutic target.
• Acquired resistance to existing BRAF and MEK inhibitors often involves the reactivation of ERK1/2 signaling, necessitating the development of new therapeutic strategies.

Purpose of the Study:

• To design and synthesize novel isoindolin-1-one derivatives as inhibitors of the ERK1/2 signaling pathway.
• To evaluate the in vitro antiproliferative activity of these compounds against cancer cell lines with specific mutations (KRAS, BRAF).
• To assess the in vivo antitumor efficacy and pharmacokinetic properties of lead compounds.

Main Methods:

• Scaffold-hopping approach was employed to generate a series of isoindolin-1-one compounds targeting ERK1/2.
• In vitro proliferation assays were conducted on KRAS and BRAF mutant cancer cell lines.
• Pharmacokinetic profiling and in vivo antitumor efficacy studies using a HCT-116 xenograft mouse model were performed for optimized compounds.

Main Results:

• The newly synthesized isoindolin-1-one compounds demonstrated potent inhibition of cancer cell proliferation at low nanomolar concentrations.
• Compound 22a exhibited favorable pharmacokinetic properties.
• Compound 22a showed significant in vivo antitumor efficacy in the HECT-116 xenograft model.

Conclusions:

• The developed isoindolin-1-one derivatives represent a promising new class of ERK1/2 inhibitors.
• Compound 22a serves as a strong preclinical candidate for further optimization towards clinical development as an anti-cancer drug.
• Targeting the ERK1/2 pathway remains a viable strategy for overcoming resistance in cancer therapy.