2. Academic Validation
  3. First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer

First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer

  • Nat Cancer. 2025 Feb;6(2):259-277. doi: 10.1038/s43018-024-00899-7.
Ramona Rudalska # 1 2,  Jule Harbig # 1 2,  Michael Forster 2 3,  Pascal Woelffing 1 2,  Aylin Esposito 1 2,  Mark Kudolo 2 3,  Adelina Botezatu 1 2,  Vanessa Haller 2 3,  Nicole Janssen 4,  Samuel Holzmayer 2 5,  Philipp Nahidino 2 3,  Omelyan Trompak 1 2,  Tatu Pantsar 2 3 6,  Thales Kronenberger 1 2 3 6,  Can Yurttas 7,  Elke Rist 1 2,  Alexander N R Weber 2 8,  Marc H Dahlke 9,  German Ott 10,  Alfred Koenigsrainer 1 2 7,  Ulrich Rothbauer 2 11 12,  Melanie Maerklin 2 5,  Thomas Muerdter 4,  Matthias Schwab 2 4 13 14,  Stephan Singer 2 15,  Lars Zender 1 2 14 16,  Stefan Laufer 2 3 16,  Daniel Dauch 17 18 19
Affiliations

Affiliations

  • 1 Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany.
  • 2 IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
  • 3 Department of Pharmaceutical Chemistry, University of Tübingen, Tübingen, Germany.
  • 4 Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany.
  • 5 Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.
  • 6 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
  • 7 Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
  • 8 Department of Immunology, University of Tübingen, Tübingen, Germany.
  • 9 Department of General and Visceral Surgery, Robert Bosch Hospital, Stuttgart, Germany.
  • 10 Department of Clinical Pathology, Robert Bosch Hospital, Stuttgart, Germany.
  • 11 NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
  • 12 Department of Pharmaceutical Biotechnology, University of Tübingen, Tübingen, Germany.
  • 13 Departments of Clinical Pharmacology, and of Biochemistry and Pharmacy, University of Tübingen, Tübingen, Germany.
  • 14 German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 15 Institute of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.
  • 16 Tübingen Center for Academic Drug Discovery and Development (TüCAD2), Tübingen, Germany.
  • 17 Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany. daniel.dauch@med.uni-tuebingen.de.
  • 18 IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany. daniel.dauch@med.uni-tuebingen.de.
  • 19 Tübingen Center for Academic Drug Discovery and Development (TüCAD2), Tübingen, Germany. daniel.dauch@med.uni-tuebingen.de.
  • # Contributed equally.
PMID: 39820127 DOI: 10.1038/s43018-024-00899-7
Abstract

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.

Figures
Products