Data availability
Source data are provided with this paper as a Source Data file. Diffraction data and crystallographic coordinates of unliganded MIFT and MITF complexed to compounds 3, 4, 6, 7, and 8 have been deposited at the protein data bank (www.rcsb.org) under accession codes 9H5F (unliganded), 9H7Q (3), 9H5H (4), 9H7R (6), 9H7T (7), and 9H7S (8). NMR resonance assignments have been deposited with the BMRB accession code 53224. All mole…
Data availability
Source data are provided with this paper as a Source Data file. Diffraction data and crystallographic coordinates of unliganded MIFT and MITF complexed to compounds 3, 4, 6, 7, and 8 have been deposited at the protein data bank (www.rcsb.org) under accession codes 9H5F (unliganded), 9H7Q (3), 9H5H (4), 9H7R (6), 9H7T (7), and 9H7S (8). NMR resonance assignments have been deposited with the BMRB accession code 53224. All molecular simulations related information, such as initial coordinate and simulation input files, along with a coordinate file of the final output were deposited in a Zenodo repository under the following link: https://doi.org/10.5281/zenodo.17611056. The synthesis of compounds 1, 3 and 5 to 9, including 1H-, 13C- and 19F-NMR analytical data, is described in the Supplementary Information file in the Supplementary Methods. Full scans of all blots and data points of RT-qPCR and cell viability experiments are deposited in the Source Data file. The RNA sequencing and Cut&Tag data has been deposited in GEO under the accession number GSE283857. Source data are provided with this paper.
Code availability
All custom cpptraj and R code used to perform the analyses and generate results in this study is publicly available and has been deposited at the following link: https://doi.org/10.5281/zenodo.17611056, without any restriction for their access and use.
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Acknowledgements
We thank Eva Altmann, Pascal Rigollier, Krystyna Patora-Komisarska and Andreas Lerchner for medicinal chemistry input and Rita Brauer, Marion Burglin and Fabien Tritsch for compound synthesis; Ayako Honda and Aragen Life Sciences Ltd. and Aurigene Pharmaceutical Services Ltd. for chemical synthesis support; Wassim Abdul Rahman, Patrizia Fontana, Catherine Zimmermann, Marco Meyerhofer and Dirk Erdmann for protein preparation and quality control; Mario Centeleghe for support with running biological experiments; Camilo Velez-Vega and Sepehr Dehghani-Ghahnaviyeh for discussion on MD simulations, and Andreas O. Frank for initial NMR experiments. We thank Sascha Gutmann and Martin Schröder for depositing the crystal structures in the protein data bank and Ulrike Naumann for her support in processing NGS samples. We are grateful to Luca Tordella for critical revision of the manuscript, and to Nicolas Soldermann and Tobias Schmelzle for their scientific guidance.
Author information
Authors and Affiliations
Novartis Biomedical Research, Basel, Switzerland
Deborah Castelletti, Jürgen Hinrichs, Goran Malojčić, Aurore Desplat, Christelle Henry, Fanny Mermet-Meillon, Markus Wartmann, Emmanuelle Wirth, Cécile Delmas, César Fernández, Niko Schmiedeberg, Simone Plattner, Jvan Brun, Stephan Kläusler, Fanny Schaeffer, Marc Altorfer, Nikoletta Piperidou, Nicolas Pautrieux, Frederic Baysang, Markus Kaufmann, Amanda Cobos-Correa, Anna Vulpetti & Wolfgang Jahnke 1.
Novartis Biomedical Research, Cambridge, MA, USA
Fei Ji & Kathryn A. Porter 1.
University of Massachusetts Amherst, Amherst, MA, USA
Bryn Reimer 1.
Technical University of Munich, Munich, Germany
Philipp H. O. Mayer 1.
ETH Zurich, Zurich, Switzerland
Jessica Kurmann 1.
Novartis Biomedical Research, Emeryville, CA, USA
Kelly Yan & John Fuller 1.
Genentech, South San Francisco, CA, USA
Danilo Maddalo 1.
Curie.Bio, Cambridge, MA, USA
Rainer Wilcken 1.
Ridgeline Discovery, Basel, Switzerland
Martin Renatus
Authors
- 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
Contributions
K.Y. and J.F. expressed and purified the proteins. C.H., C.D., P.M., C.F., and W.J. designed and performed NMR experiments. E.W. and M.R. solved crystal structures. A.V., R.W., J.H., and N.S. designed compounds. S.P., J.B., S.K., and J.K. synthesized compounds. N.Pi., N.Pa., F.B., and G.M. designed and performed SPR, ITC and nanoDSF experiments. A.V. designed the LEF4000 library. A.V., K.P., and B.R. devised and performed MD simulations. F.J. conducted the statistical analysis of bulk RNA-seq, scRNA-seq and Cut&Tag (from patient samples or preclinical experiments). A.D., F.M.M., M.W., D.M., M.A., F.S., M.K., and A.C.C. generated biology data. D.C., J.H., W.J., M.R., A.V., and G.M. devised the project strategy. D.C., A.V., J.H., G.M., and W.J. wrote the manuscript, with input from other co-authors.
Corresponding authors
Correspondence to Deborah Castelletti, Jürgen Hinrichs, Goran Malojčić, Anna Vulpetti or Wolfgang Jahnke.
Ethics declarations
Competing interests
D.C., A.V., J.H., G.M., W.J., F.J., K.Y., J.F., C.H., C.D., C.F., E.W., N.S., S.P., J.B., S.K., N.Pi., N.Pa., F.B., K.P., A.D., F.M.M., M.W., M.A., F.S., M.K., and A.C.C. are employees and shareholders of Novartis Pharma. P.H.O.M., J.K., R.W., M.R., D.M., and B.R. are former employees of Novartis AG.
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Castelletti, D., Hinrichs, J., Malojčić, G. et al. Fragment-based discovery enables direct targeting of the melanoma oncogene MITF. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67297-0
Received: 10 November 2024
Accepted: 26 November 2025
Published: 09 December 2025
DOI: https://doi.org/10.1038/s41467-025-67297-0