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<p>Despite the improvement of therapeutic options, melanoma patients with advanced metastatic disease are still in high need of durable treatments. Analysis of clinical data from patients receiving targeted and/or immunotherapy, along with genetic and functional studies in preclinical melanoma models, demonstrates the key role of the microphthalmia-associated transcription factor (MITF) throughout disease progression, and provides a solid rationale for its therapeutic inhibition. However, direct targeting of MITF or other basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors is unprecedented. Here, we report on the discovery of ligands for the DNA binding domain of MITF, using fragment-based screening (FBS) by nuclear magnetic resonance (NMR). Initial fragments, binding the kink pocket of MITF very weakly, are optimized to sub-micromolar affinities by structure-based design enabled by X-ray crystallography and biophysics. Furthermore, NMR experiments and molecular dynamics simulations reveal a dynamic conformational exchange between helices in the asymmetric homodimer, a phenomenon that is perturbed by ligand binding. This work advances our knowledge on direct targeting of bHLH-LZ DNA binding domains and sets the basis to further explore pharmacological inhibition of MITF.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月9日

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  • Deborah Castelletti,
  • Jürgen Hinrichs,
  • Goran Malojčić,
  • Fei Ji,
  • Aurore Desplat,
  • Bryn Reimer,
  • Christelle Henry,
  • Kathryn A. Porter,
  • Fanny Mermet-Meillon,
  • Markus Wartmann,
  • Emmanuelle Wirth,
  • Cécile Delmas,
  • César Fernández,
  • Philipp H. O. Mayer,
  • Niko Schmiedeberg,
  • Simone Plattner,
  • Jvan Brun,
  • Stephan Kläusler,
  • Jessica Kurmann,
  • Kelly Yan,
  • John Fuller,
  • Fanny Schaeffer,
  • Danilo Maddalo,
  • Marc Altorfer,
  • Nikoletta Piperidou,
  • Nicolas Pautrieux,
  • Frederic Baysang,
  • Markus Kaufmann,
  • Amanda Cobos-Correa,
  • Rainer Wilcken,
  • Martin Renatus,
  • Anna Vulpetti,
  • Wolfgang Jahnke

摘要

Despite the improvement of therapeutic options, melanoma patients with advanced metastatic disease are still in high need of durable treatments. Analysis of clinical data from patients receiving targeted and/or immunotherapy, along with genetic and functional studies in preclinical melanoma models, demonstrates the key role of the microphthalmia-associated transcription factor (MITF) throughout disease progression, and provides a solid rationale for its therapeutic inhibition. However, direct targeting of MITF or other basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors is unprecedented. Here, we report on the discovery of ligands for the DNA binding domain of MITF, using fragment-based screening (FBS) by nuclear magnetic resonance (NMR). Initial fragments, binding the kink pocket of MITF very weakly, are optimized to sub-micromolar affinities by structure-based design enabled by X-ray crystallography and biophysics. Furthermore, NMR experiments and molecular dynamics simulations reveal a dynamic conformational exchange between helices in the asymmetric homodimer, a phenomenon that is perturbed by ligand binding. This work advances our knowledge on direct targeting of bHLH-LZ DNA binding domains and sets the basis to further explore pharmacological inhibition of MITF.