Structure-based design of new potent and highly selective PARP-1 inhibitor for treating colorectal cancer

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Poly (ADP-ribose) polymerase 1 (PARP-1) is overexpressed in colorectal cancer (CRC) and plays a crucial role in DNA damage repair.
• PARP-1 is a promising therapeutic target for CRC treatment.

Purpose of the Study:

• To identify novel, potent, and selective inhibitors of PARP-1.
• To evaluate the efficacy of identified inhibitors in colorectal cancer models.

Main Methods:

• Pharmacophore modeling and virtual screening were employed to identify potential PARP-1 inhibitors.
• Enzyme inhibition assays, molecular dynamic simulations, and cellular proliferation assays were conducted for biological evaluation.

Main Results:

• Compound-5 demonstrated significant inhibition of PARP-1 activity with an IC50 of 0.07 ± 0.01 nM.
• Compound-5 exhibited high selectivity for PARP-1 over 63 other kinases.
• Molecular dynamics simulations confirmed stable binding of compound-5 to the PARP-1 catalytic domain.
• Compound-5 effectively inhibited the proliferation of multiple human CRC cell lines.

Conclusions:

• Compound-5 is a highly potent and selective PARP-1 inhibitor.
• Compound-5 shows significant anti-proliferative effects on CRC cells.
• Compound-5 represents a promising therapeutic candidate for colorectal cancer treatment.