Irreversible inhibitors of the epidermal growth factor receptor: thienopyrimidine core with α,β-unsaturated amide...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Epidermal growth factor receptor (EGFR) tyrosine kinase overexpression is linked to poor prognosis in various cancers.
• Developing effective irreversible inhibitors for EGFR family kinases, particularly HER2, is crucial for cancer treatment.

Purpose of the Study:

• To design and synthesize novel thieno[2,3-d]pyrimidine derivatives as irreversible HER2 tyrosine kinase inhibitors.
• To investigate structure-activity relationships by varying substituents at the 4-position of the thienopyrimidine core.
• To evaluate the inhibitory potential and anti-proliferative activity of the synthesized compounds against HER2-positive cancer cells.

Main Methods:

• Synthesis of two series of HER2 tyrosine kinase inhibitors based on thieno[3,2-d]pyridine and thieno[2,3-d]pyridine scaffolds.
• Incorporation of a basic α,β-unsaturated amide side chain as a Michael acceptor for covalent binding to Cys773 in the EGFR enzyme's ATP binding pocket.
• Evaluation of enzyme inhibition and anti-proliferative effects of the compounds against SK-BR-3 cells.

Main Results:

• Thieno[2,3-d]pyrimidine derivatives (16a-d) exhibited potent HER2 enzyme inhibition and anti-proliferative activity.
• Compound (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)thieno[2,3-d]pyrimidin-6-yl)-4-(dimethylamino)but-2-enamide (16d) was identified as a promising irreversible HER2 inhibitor.
• Compound 16d demonstrated superior catalytic enzyme activity and cellular efficacy compared to the marketed drug lapatinib.

Conclusions:

• The thieno[2,3-d]pyrimidine scaffold is effective for developing potent irreversible HER2 inhibitors.
• Compound 16d represents a potential therapeutic agent for HER2-positive cancers, offering advantages over existing treatments.
• Further investigation into compound 16d is warranted for its clinical development.