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Nature cancer
Feb, 2025;6 (2): 259-277.

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

Ramona Rudalska, Jule Harbig, Michael Forster, Pascal Woelffing, Aylin Esposito, Mark Kudolo, Adelina Botezatu, Vanessa Haller, Nicole Janssen, Samuel Holzmayer, Philipp Nahidino, Omelyan Trompak, Tatu Pantsar, Thales Kronenberger, Can Yurttas, Elke Rist, Alexander N R Weber, Marc H Dahlke, German Ott, Alfred Koenigsrainer, Ulrich Rothbauer, Melanie Maerklin, Thomas Muerdter, Matthias Schwab, Stephan Singer, Lars Zender, Stefan Laufer, Daniel Dauch
Author Information
  1. Ramona Rudalska: Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany. ORCID
  2. Jule Harbig: Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany.
  3. Michael Forster: IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany. ORCID
  4. Pascal Woelffing: Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany.
  5. Aylin Esposito: Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany.
  6. Mark Kudolo: IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
  7. Adelina Botezatu: Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany.
  8. Vanessa Haller: IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
  9. Nicole Janssen: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany.
  10. Samuel Holzmayer: IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany. ORCID
  11. Philipp Nahidino: IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
  12. Omelyan Trompak: Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany.
  13. Tatu Pantsar: IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany. ORCID
  14. Thales Kronenberger: Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany. ORCID
  15. Can Yurttas: Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany.
  16. Elke Rist: Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany.
  17. Alexander N R Weber: IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany. ORCID
  18. Marc H Dahlke: Department of General and Visceral Surgery, Robert Bosch Hospital, Stuttgart, Germany.
  19. German Ott: Department of Clinical Pathology, Robert Bosch Hospital, Stuttgart, Germany.
  20. Alfred Koenigsrainer: Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany.
  21. Ulrich Rothbauer: IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
  22. Melanie Maerklin: IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany. ORCID
  23. Thomas Muerdter: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany.
  24. Matthias Schwab: IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany. ORCID
  25. Stephan Singer: IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
  26. Lars Zender: Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany. ORCID
  27. Stefan Laufer: IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
  28. Daniel Dauch: Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany. daniel.dauch@med.uni-tuebingen.de. ORCID
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.

References

  1. Anal Biochem. 2010 Nov 15;406(2):233-4 [PMID: 20638357]
  2. EMBO J. 1997 Jun 16;16(12):3563-71 [PMID: 9218798]
  3. Int J Mol Sci. 2020 Mar 11;21(6): [PMID: 32168915]
  4. Nat Rev Cancer. 2009 Aug;9(8):537-49 [PMID: 19629069]
  5. Trends Biochem Sci. 2000 Jun;25(6):257-60 [PMID: 10838561]
  6. Trends Cell Biol. 2006 Jun;16(6):285-92 [PMID: 16682204]
  7. Nat Commun. 2022 Jan 28;13(1):569 [PMID: 35091547]
  8. Nat Biotechnol. 2017 Jun;35(6):569-576 [PMID: 28459449]
  9. Mol Cancer Ther. 2014 Feb;13(2):364-74 [PMID: 24356814]
  10. Nature. 2014 Oct 16;514(7522):380-4 [PMID: 25119044]
  11. Nat Rev Clin Oncol. 2021 Aug;18(8):506-525 [PMID: 33864051]
  12. Nat Med. 2015 Nov;21(11):1350-6 [PMID: 26457759]
  13. CA Cancer J Clin. 2024 May-Jun;74(3):229-263 [PMID: 38572751]
  14. Nature. 2009 May 14;459(7244):262-5 [PMID: 19329995]
  15. Acta Crystallogr D Biol Crystallogr. 2009 Aug;65(Pt 8):777-85 [PMID: 19622861]
  16. Lancet. 2019 Oct 19;394(10207):1467-1480 [PMID: 31631858]
  17. J Med Chem. 2010 Mar 25;53(6):2345-53 [PMID: 19950901]
  18. Nature. 2011 Nov 09;479(7374):547-51 [PMID: 22080947]
  19. Mol Biol Cell. 2012 Dec;23(23):4515-25 [PMID: 23051732]
  20. Anal Biochem. 2005 Aug 1;343(1):76-83 [PMID: 15979553]
  21. Angew Chem Int Ed Engl. 2018 Apr 9;57(16):4372-4385 [PMID: 28994500]
  22. World J Gastroenterol. 2014 Aug 7;20(29):9744-58 [PMID: 25110412]
  23. Nat Rev Immunol. 2006 Jul;6(7):532-40 [PMID: 16799472]
  24. J Med Chem. 2006 Oct 19;49(21):6177-96 [PMID: 17034125]
  25. Nat Med. 2016 Jul;22(7):744-53 [PMID: 27213815]
  26. J Med Chem. 2017 Oct 12;60(19):8027-8054 [PMID: 28834431]
  27. Clin Cancer Res. 2016 Mar 1;22(5):1095-102 [PMID: 26581242]
  28. Cell. 2008 Aug 22;134(4):657-67 [PMID: 18724938]
  29. Nat Cancer. 2021 Oct;2(10):1071-1085 [PMID: 34738089]
  30. Nat Rev Drug Discov. 2022 Dec;21(12):881-898 [PMID: 36008483]
  31. Therap Adv Gastroenterol. 2020 Jun 1;13:1756284820917527 [PMID: 32536977]
  32. Nat Biotechnol. 2017 Apr;35(4):350-353 [PMID: 28263295]
  33. J Cell Biol. 2009 Apr 20;185(2):193-202 [PMID: 19364923]
  34. Nat Struct Biol. 2002 Apr;9(4):268-72 [PMID: 11896401]
  35. Cell Rep. 2013 Dec 26;5(6):1704-13 [PMID: 24332856]
  36. Nature. 2001 May 3;411(6833):102-7 [PMID: 11333986]
  37. Cell Cycle. 2006 Aug;5(15):1649-53 [PMID: 16861915]
  38. Signal Transduct Target Ther. 2020 Mar 20;5(1):22 [PMID: 32296018]
  39. Nat Rev Gastroenterol Hepatol. 2019 Jan;16(1):19-34 [PMID: 30429586]
  40. Lancet. 2020 Mar 28;395(10229):1078-1088 [PMID: 32222192]
  41. Nat Rev Mol Cell Biol. 2021 May;22(5):346-366 [PMID: 33504982]
  42. Clin Gastroenterol Hepatol. 2006 Mar;4(3):325-34 [PMID: 16527696]
  43. Cell. 1992 Mar 6;68(5):855-67 [PMID: 1547487]
  44. Cancer Discov. 2023 Jun 2;13(6):1454-1477 [PMID: 36883955]
  45. Cell Div. 2007 May 04;2:12 [PMID: 17480229]
  46. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17059-64 [PMID: 16286660]
  47. Nature. 2018 Oct;562(7725):69-75 [PMID: 30209397]
  48. Nat Cancer. 2021 Feb;2(2):201-217 [PMID: 35122079]
  49. Bioorg Med Chem Lett. 2011 Jul 1;21(13):4066-71 [PMID: 21641211]
  50. Biochim Biophys Acta. 2007 Aug;1773(8):1358-75 [PMID: 17481747]
  51. EMBO J. 1998 Mar 16;17(6):1740-9 [PMID: 9501095]
  52. Eur J Med Chem. 2017 Sep 29;138:96-114 [PMID: 28651155]
  53. Cancer Cell. 2014 Apr 14;25(4):484-500 [PMID: 24684847]
  54. ACS Chem Biol. 2014 Jun 20;9(6):1230-41 [PMID: 24730530]
  55. Angew Chem Int Ed Engl. 2017 May 2;56(19):5363-5367 [PMID: 28397331]
  56. Nat Chem Biol. 2011 Dec 25;8(2):141-3 [PMID: 22198732]
  57. Signal Transduct Target Ther. 2021 May 31;6(1):201 [PMID: 34054126]
  58. Nat Med. 2014 Oct;20(10):1138-46 [PMID: 25216638]
  59. Eur J Med Chem. 2022 May 5;235:114234 [PMID: 35325634]
  60. N Engl J Med. 2022 Jun 23;386(25):2363-2376 [PMID: 35660797]
  61. Nat Rev Cancer. 2022 Jun;22(6):340-355 [PMID: 35241831]

Grants

  1. 490941264/Deutsche Forschungsgemeinschaft (German Research Foundation)
  2. FOR2314/Deutsche Forschungsgemeinschaft (German Research Foundation)
  3. SFB-TR209 - 314905040/Deutsche Forschungsgemeinschaft (German Research Foundation)
  4. EXC 2180 - 390900677/Deutsche Forschungsgemeinschaft (German Research Foundation)
  5. SFB-TR240/Deutsche Forschungsgemeinschaft (German Research Foundation)
  6. Gottfried Wilhelm Leibniz Program/Deutsche Forschungsgemeinschaft (German Research Foundation)

MeSH Term

Colorectal Neoplasms
Humans
Animals
Mitogen-Activated Protein Kinase 14
Mice
Mitosis
Protein Kinase Inhibitors
Apoptosis
Cell Line, Tumor
Xenograft Model Antitumor Assays
Protein-Tyrosine Kinases
Cell Cycle Proteins
Female
Molecular Targeted Therapy

Chemicals

Mitogen-Activated Protein Kinase 14
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Cell Cycle Proteins
WEE1 protein, human
Journal Article
Article has an altmetric score of 4

Word Cloud

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