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

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.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2025-12-09
DOI
https://doi.org/10.1038/s41467-025-67297-0
Primary Topic
Melanoma and MAPK Pathways
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Markus Kaufmann, Markus Wartmann, Danilo Maddalo, John Fuller et al.
Nature Communications
Melanoma and MAPK Pathways
article

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

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

Abstract

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.

Nature CommunicationsVol. 17(1)
Novartis (Switzerland) (CH), Biogen (United States) (US), University of Massachusetts Amherst (US), ETH Zurich (CH), Novartis (United States) (US), Med Discovery (Switzerland) (CH), Novartis Foundation (CH), Technical University of Munich (DE)
Openalex Percentile: Top 64%
Melanoma and MAPK Pathways
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.