First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer
Colorectal cancer (CRC) constitutes the second leading cause of cancer-related death worldwide and advanced CRCs are resistant to targeted therapies, chemotherapies and immunotherapies. p38α (Mapk14) has been suggested as a therapeutic target in CRC; however, available p38α inhibitors only allow for insufficient target inhibition. Here we describe a unique class of p38α inhibitors with ultralong target residence times (designated ULTR-p38i) that robustly inhibit p38α downstream signaling and induce distinct biological phenotypes. ULTR-p38i monotherapy triggers an uncontrolled mitotic entry by activating Cdc25 and simultaneously blocking Wee1. Consequently, CRC cells undergo mitotic catastrophe, resulting in apoptosis or senescence. ULTR-p38i exhibit high selectivity, good pharmaco-kinetic properties and no measurable toxicity with strong therapeutic effects in patient-derived CRC organoids and syngeneic CRC mouse models. Conceptually, our study suggests ultralong-target-residence-time kinase inhibitors as an alternative to covalent inhibitors, which, because of the lack of cysteine residues, cannot be generated for many kinase cancer targets.
Authors
- Thomas Muerdter
- Vanessa Haller
- Mark Kudolo
- Ramona Rudalska (ORCID: https://orcid.org/0000-0002-1742-0912)
- Pascal Woelffing
- Alfred Koenigsrainer
- Alexander N.R. Weber (ORCID: https://orcid.org/0000-0002-8627-7056)
- Omelyan Trompak
- Tatu Pantsar (ORCID: https://orcid.org/0000-0002-0369-2909)
- Stefan Laufer (ORCID: https://orcid.org/0000-0001-6952-1486)
- Philipp Nahidino
- Samuel J. Holzmayer (ORCID: https://orcid.org/0009-0006-4513-2367)
- A. Botezatu
- Can Yurttas (ORCID: https://orcid.org/0000-0001-9720-8243)
- Lars Zender (ORCID: https://orcid.org/0000-0001-7626-2849)
- Elke Rist
- Jule Harbig (ORCID: https://orcid.org/0000-0001-8171-3843)
- Matthias Schwab (ORCID: https://orcid.org/0000-0002-9984-075X)
- Ulrich Rothbauer (ORCID: https://orcid.org/0000-0001-5923-8986)
- German Ott (ORCID: https://orcid.org/0000-0001-7990-6793)
- Daniel Dauch (ORCID: https://orcid.org/0000-0002-9805-5784)
- Thales Kronenberger (ORCID: https://orcid.org/0000-0001-6933-7590)
- Annachiara Esposito (ORCID: https://orcid.org/0000-0002-5017-1954)
- Melanie Märklin (ORCID: https://orcid.org/0000-0002-2920-3894)
- Michael Förster (ORCID: https://orcid.org/0009-0008-7446-3733)
- Nicole Janssen (ORCID: https://orcid.org/0000-0002-3117-5984)
- Stephan Singer (ORCID: https://orcid.org/0000-0003-4775-6609)
- Marc H. Dahlke
Institutions
- University of Eastern Finland (FI)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Robert Bosch Hospital (DE)
- Natural and Medical Sciences Institute (DE)
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE)
- University Children's Hospital Tübingen (DE)
- Bernstein Center for Computational Neuroscience Tübingen (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- University of Tübingen (DE)
Publication Details
- Journal
- Nature Cancer
- Published
- 2025-01-16
- DOI
- https://doi.org/10.1038/s43018-024-00899-7
- Citations
- 11
- Primary Topic
- Colorectal Cancer Treatments and Studies
- Type
- article
- Field-Weighted Citation Impact
- 11.50
Funders
- Deutsche Forschungsgemeinschaft