First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer PMID: 39820127

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
18. IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany. [email protected].
19. Tübingen Center for Academic Drug Discovery and Development (TüCAD2), Tübingen, Germany. [email protected].
# Contributed equally.

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.