Pomalidomide hybrids act as proteolysis targeting chimeras: Synthesis, anticancer activity and B-Raf degradation

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• B-Raf is a frequently mutated oncogene and a critical target in cancer therapy.
• Developing novel therapeutic strategies to target B-Raf is essential for effective cancer treatment.

Purpose of the Study:

• To design and synthesize novel pomalidomide-based PROTACs for targeted B-Raf degradation.
• To evaluate the efficacy of these PROTACs in degrading B-Raf and inducing cancer cell death.

Main Methods:

• Synthesis of pomalidomide-B-Raf PROTAC hybrids.
• Assessment of B-Raf degradation in cancer cells using PROTACs.
• Evaluation of cancer cell viability and apoptosis induction by PROTACs.
• Analysis of downstream protein expression, including Mcl-1.

Main Results:

• Several pomalidomide hybrids demonstrated PROTAC activity, leading to B-Raf degradation.
• MCF-7 cells, with high B-Raf expression, were sensitive to the PROTACs.
• Compound 2 effectively induced apoptosis and cell death in cancer cells.
• Compound 2 accelerated B-Raf degradation via the ubiquitin-proteasome system and affected Mcl-1 expression.

Conclusions:

• PROTAC-mediated degradation of B-Raf is a promising strategy for cancer therapy.
• Compound 2 exhibits potent anti-cancer activity through B-Raf degradation and apoptosis induction.
• Targeting B-Raf degradation offers a distinct and potentially more effective approach compared to traditional B-Raf inhibitors.