Ultralong-target-residence-time p38alpha inhibitors for combinatorial cancer therapies

01/10/2026 to 30/09/2029

Therapy resistance remains a major obstacle to the effective treatment of patients with solid tumors. Despite significant advances in the identification of molecular targets and the development of immunotherapies, clinical outcomes for patients with advanced solid malignancies often remain poor. Consequently, therapy-resistant tumor entities, including colorectal cancer (CRC), hepatocellular carcinoma (HCC), and pancreatic ductal adenocarcinoma (PDAC), continue to pose a major global health challenge, accounting for millions of deaths worldwide each year. The development of new and more effective therapeutic strategies for these malignancies is therefore urgently needed.

We recently developed and tested a novel class of p38α inhibitors with very high affinities and ultralong-target-residence-times (ULTR-p38i). This unique combination enables significantly extended binding and highly efficient inhibition of the target molecule, allowing ULTR-p38i to efficiently block even overactivated p38 signaling. In strong contrast to earlier generations of p38α inhibitors, these novel ULTR-p38i trigger strong therapeutic effects in CRC. An ULTR-p38i therapy results in marked tumor remissions and increased survival of mice in organoid-based CRC mouse models and triggers strong therapeutic effects in different patient-derived organoid cultures. ULTR-p38i induce an uncontrolled mitotic entry resulting in repeating cycles of mitotic catastrophe, strong induction of aneuploidy, DNA damage and finally in apoptosis or senescence in cancer cells. Since these inhibitors also exhibit high selectivity, high stability in vivo and are well tolerated by mice (Rudalska et al., 2025), they have a very strong potential for the treatment of cancer patients in the future.

However, ULTR-p38i monotherapy does not entirely cure mice suffering from advanced colorectal cancer and development of therapy resistance limits the long-term therapeutic effect of ULTR-p38i. With this project, we therefore aim to enhance the therapeutic efficacy of ULTR-p38i by establishing efficient combinatorial therapies. Furthermore, we aim to test ULTR-p38i-based therapies in other tumor entities such as hepatocellular carcinoma and pancreatic ductal adenocarcinoma to expand the scope of ULTR-p38i. Overall, this project will play an important role in the development of effective anti-mitotic cancer therapies to overcome therapy resistance in solid tumors.