Fragment-based discovery enables direct targeting of the melanoma oncogene MITF

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Advanced metastatic melanoma lacks durable treatment options.
• The microphthalmia-associated transcription factor (MITF) plays a crucial role in melanoma progression.
• Targeting transcription factors like MITF presents a significant therapeutic challenge.

Purpose of the Study:

• To discover ligands that can directly target the DNA binding domain of MITF.
• To establish a foundation for the pharmacological inhibition of MITF in melanoma treatment.

Main Methods:

• Fragment-based screening (FBS) using nuclear magnetic resonance (NMR) to identify initial MITF-binding fragments.
• Structure-based design, X-ray crystallography, and biophysical techniques to optimize fragment affinity.
• NMR experiments and molecular dynamics simulations to elucidate ligand-induced conformational changes.

Main Results:

• Identified initial weak-binding fragments for the MITF kink pocket.
• Optimized fragments to achieve sub-micromolar affinities through structure-based design.
• Revealed ligand-induced perturbation of dynamic conformational exchange in the MITF homodimer.

Conclusions:

• Demonstrated the feasibility of directly targeting the DNA binding domain of basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors.
• Established a basis for developing novel therapeutic strategies targeting MITF in melanoma.
• Advanced the understanding of protein-ligand interactions involving dynamic protein conformations.