Discovery of Novel and Potent Dual PARP1/ERK Inhibitors as a Promising Strategy for Cancer Therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Clinical use of poly(ADP-ribose) polymerase 1 (PARP1) inhibitors is limited by drug resistance and efficacy.
• The extracellular signal-regulated kinase (ERK) pathway can be suppressed to impair homologous recombination (HR) repair, sensitizing cancer cells to PARP1 inhibition.

Purpose of the Study:

• To design and develop a novel dual inhibitor targeting both PARP1 and ERK.
• To evaluate the efficacy of this dual inhibitor in preclinical cancer models.

Main Methods:

• Design and synthesis of a novel dual PARP1/ERK inhibitor, I-16.
• In vitro assessment of PARP1 and ERK2 inhibition (IC50 values).
• Evaluation of antiproliferative activity in various cancer cell lines (BRCA mutant and wild-type).
• In vivo efficacy study using an HCT116 xenograft model.

Main Results:

• I-16 demonstrated potent and selective inhibition of PARP1 (IC50 = 0.9 nM) and ERK2 (IC50 = 1.8 nM).
• I-16 exhibited significant antiproliferative effects across diverse cancer cell lines.
• In vivo, I-16 significantly suppressed tumor growth in an HCT116 xenograft model, outperforming monotherapies and showing comparable efficacy to combination treatments.

Conclusions:

• I-16 is the first potent dual PARP1/ERK inhibitor developed.
• This dual inhibition strategy effectively targets cancer cells, including those resistant to other therapies.
• I-16 represents a promising therapeutic candidate for cancer treatment.