{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["17(1)"],"submitter":["Castelletti D"],"pubmed_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."],"journal":["Nature communications"],"pagination":["594"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12808237"],"repository":["biostudies-literature"],"pubmed_title":["Fragment-based discovery enables direct targeting of the melanoma oncogene MITF."],"pmcid":["PMC12808237"],"pubmed_authors":["Mayer PHO","Henry C","Plattner S","Maddalo D","Reimer B","Piperidou N","Castelletti D","Mermet-Meillon F","Kurmann J","Klausler S","Yan K","Altorfer M","Hinrichs J","Jahnke W","Ji F","Porter KA","Delmas C","Wartmann M","Kaufmann M","Fernandez C","Malojcic G","Desplat A","Brun J","Schmiedeberg N","Cobos-Correa A","Schaeffer F","Vulpetti A","Renatus M","Baysang F","Pautrieux N","Wilcken R","Wirth E","Fuller J"],"additional_accession":[]},"is_claimable":false,"name":"Fragment-based discovery enables direct targeting of the melanoma oncogene MITF.","description":"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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Dec","modification":"2026-06-10T05:23:20.932Z","creation":"2026-06-10T03:07:21.684Z"},"accession":"S-EPMC12808237","cross_references":{"pubmed":["41365902"],"doi":["10.1038/s41467-025-67297-0"]}}