Rudalska Ramona, Harbig Jule, Forster Michael, Woelffing Pascal, Esposito Aylin, Kudolo Mark, Botezatu Adelina, Haller Vanessa, Janssen Nicole, Holzmayer Samuel, Nahidino Philipp, Trompak Omelyan, Pantsar Tatu, Kronenberger Thales, Yurttas Can, Rist Elke, Weber Alexander N R, Dahlke Marc H, Ott German, Koenigsrainer Alfred, Rothbauer Ulrich, Maerklin Melanie, Muerdter Thomas, Schwab Matthias, Singer Stephan, Zender Lars, Laufer Stefan, Dauch Daniel
Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen, Germany.
IFIT Cluster of Excellence EXC 2180 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
Nat Cancer. 2025 Feb;6(2):259-277. doi: 10.1038/s43018-024-00899-7. Epub 2025 Jan 16.
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.
结直肠癌（CRC）是全球癌症相关死亡的第二大主要原因，晚期CRC对靶向治疗、化疗和免疫治疗均具有抗性。p38α（Mapk14）已被认为是CRC的一个治疗靶点；然而，现有的p38α抑制剂仅能实现对靶点的不完全抑制。在此，我们描述了一类独特的具有超长靶点驻留时间的p38α抑制剂（命名为ULTR-p38i），其能强有力地抑制p38α下游信号传导并诱导不同的生物学表型。ULTR-p38i单药治疗通过激活Cdc25并同时阻断Wee1触发不受控制的有丝分裂进入。因此，CRC细胞会发生有丝分裂灾难，导致凋亡或衰老。ULTR-p38i在患者来源的CRC类器官和同基因CRC小鼠模型中表现出高选择性、良好的药代动力学特性且无明显毒性，并具有强大的治疗效果。从概念上讲，我们的研究表明超长靶点驻留时间的激酶抑制剂可作为共价抑制剂的替代物，由于缺乏半胱氨酸残基，许多激酶癌症靶点无法生成共价抑制剂。
