Design, synthesis and anti-breast cancer activity evaluation of 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-based...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Poly (ADP-ribose) polymerase 1 (PARP1) inhibitors are approved for BRCA1/2-mutated breast cancer.
• Limited efficacy and resistance issues exist for PARP1 inhibitors in wild-type cancers.

Purpose of the Study:

• To design novel 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-based compounds as potential PARP1/ATR dual inhibitors.
• To evaluate the antitumor activity and mechanism of action of these novel compounds in breast cancer.

Main Methods:

• Synthesis and chemical modification of pyrrolo[3,4-d]pyrimidine derivatives.
• In vitro evaluation of PARP1 and ATR inhibitory activity (IC50 values).
• Assessment of antitumor effects in breast cancer cell lines (MDA-MB-231, MDA-MB-468), including cell cycle, apoptosis, colony formation, migration, and DNA damage repair inhibition.

Main Results:

• Compound 38a demonstrated potent dual PARP1/ATR inhibition (IC50 < 20 nM).
• 38a exhibited significant in vitro antitumor activity against MDA-MB-231 (IC50 < 0.048 μM) and MDA-MB-468 (IC50: 0.01 μM) cells.
• Mechanistic studies showed 38a induced cell cycle arrest, apoptosis, inhibited colony formation and migration, and suppressed DNA damage repair, outperforming Niraparib plus AZD6738 combination therapy.

Conclusions:

• Novel pyrrolo[3,4-d]pyrimidine derivatives can be developed as potent PARP1/ATR dual inhibitors.
• Compound 38a shows promising therapeutic potential for breast cancer treatment.
• Further investigation into PARP1/ATR dual inhibitors is warranted for overcoming resistance and improving efficacy in breast cancer.