Summary
The p38α (Mapk14) kinase belongs to the Mitogen-activated protein kinases and can be activated by environmental stress and pro-inflammatory cytokines. Due to its role in inflammation, oncogenic signaling pathways, autophagy, and the tumor microenvironment, a potential role of p38α in cancer was suggested. However, currently available p38α inhibitors do not allow for a sufficient target inhibition in cancer cells. Consequently, no p38α inhibitor has been approved for the treatment of cancer patients so far.
In an extensive drug discovery program of TüCAD2 and IFIT, we developed and tested a novel class of inhibitors targeting p38α with very high affinity, remarkable selectivity and ultralong drug–target residence times. These novel compounds were designated as ULTR-p38i. In strong contrast to earlier generations of p38α inhibitors, these novel ULTR-p38i show as a monotherapy strong therapeutic efficacy in different cancer entities such as colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC).
ULTR-p38i strongly inhibit p38α downstream signaling, preventing phosphorylation of MAPKAPK2 (MK2) and thereby influencing important regulators of the mitotic entry in cancer cells. Consequently, ULTR-p38i-treated cancer cells undergo an uncontrolled mitosis, show multipolar spindles and mitotic catastrophe, leading to aneuploidy/polyploidy, DNA damage and finally to apoptosis or senescence. An ULTR-p38i therapy results in marked tumor remissions in therapy resistant, predictive cancer models in vivo and allow for an efficient inhibition of genetically different patient-derived cancer organoid cultures. Since our data indicate good tolerability of ULTR-p38i in patients, our goal is now to bring this promising therapeutic strategy into clinical application.
Overall, such ultralong drug–target residence time kinase inhibitors might represent an alternative to covalent inhibitors, which are difficult to generate for many kinases due to a lack of suitably positioned cysteine residues.
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