Novel tertiary sulfonamides as potent anti-cancer agents

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Breast cancer is the most common cancer in US women.
• Targeting dysregulated signal transduction pathways offers effective anti-cancer strategies.
• The Wingless-related integration site (Wnt) pathway is frequently dysregulated in breast cancer.

Purpose of the Study:

• To optimize a "hit" compound identified from a screening campaign for Wnt pathway inhibition.
• To develop potent and drug-like molecules targeting the Wnt pathway for breast cancer treatment.

Main Methods:

• Screening of 76,000 compounds in a Wnt transcription assay to identify a "hit" compound (compound 1).
• Medicinal chemistry optimization of compound 1 to generate novel analogs (compounds 19, 24, 25).
• Evaluation of Wnt pathway inhibition (IC50 values) and anti-proliferative activity in breast cancer cell lines (MCF-7, MDA-MB 231).
• Assessment of compound 19's synergistic effect with Doxorubicin in vitro and in a xenograft animal model.

Main Results:

• Optimized compounds 19, 24, and 25 demonstrated potent Wnt pathway inhibition with IC50 values in the nanomolar range.
• Compounds 19, 24, and 25 exhibited significant anti-proliferative activity against MCF-7 and MDA-MB 231 breast cancer cell lines.
• Compound 19 showed synergistic anti-proliferative effects when combined with Doxorubicin in vitro.
• Compound 19 enhanced the anti-proliferative efficacy of Doxorubicin in a breast cancer xenograft animal model.

Conclusions:

• Medicinal chemistry optimization successfully yielded potent Wnt pathway inhibitors with improved drug-like properties.
• Compounds 19, 24, and 25 represent promising therapeutic candidates for breast cancer treatment by targeting the Wnt pathway.
• Compound 19 demonstrates potential as an adjuvant therapy, enhancing the efficacy of conventional chemotherapeutics like Doxorubicin.