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<p>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 (<i>Mapk14</i>) 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月16日

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  • 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

摘要

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.