Summary

Therapeutic options for patients with advanced colorectal cancer (CRC) are still limited, resulting in median survival times of only two years after diagnosis. Recent data revealed Mapk14 (p38α) as a powerful therapeutic target for the treatment of CRC. Genetic ablation of p38α induced death of CRC cells and resulted in increased survival of CRC bearing mice. However, clinical translation was hampered by the fact, that current small molecule inhibitors of p38α have limited target residency time, thus only allowing for incomplete p38α pathway inhibition and limited therapeutic efficacy. We recently reported a novel class of p38α inhibitors with target residency times >4000s, allowing full inhibition of p38α signaling. From these molecules a unique and proprietary collection of 500 molecules with drug like properties was recently generated.
Bringing together a team of experts with complementary expertise in academic drug development, we will combine well-established p38α in silico and biochemical screening assays (Laufer) with functional in vitro high content analysis to monitor p38α downstream signaling, apoptosis and cell viability (Rothbauer) in order to identify potential clinical candidates. Prioritized inhibitors will be synthesized in medium scale (Laufer) and subjected to pharmacokinetic studies and functional testing in patient derived CRC organoid cultures and CRC mouse models (Dauch and Zender). We envision that our herein proposed research will lead to a clinical candidate, which will be tested in a phase I/II trial (funded by alternative sources).

Funded by the Landesstiftung BW

Prof. Dr. Stefan Laufer
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy
Eberhard-Karls-University of Tübingen
Auf der Morgenstelle 8, 72076 Tübingen
Tel.: +49(0)7071 29-78788
Fax: +49(0)7071 29-5037
Stefan.laufer@uni-tuebingen.de

Prof. Dr. Ulrich Rothbauer
Natural and Medical Sciences Institute (NMI)
Markwiesenstrasse 55, 72770 Reutlingen
Tel.: +49(0)7212 51530415
Fax: +49(0)7121 5153016
Ulrich.rothbauer@nmi.de

Prof. Dr. Lars Zender
Department of Internal Medicine VIII and Department of Vegetative and Clinical Physiology,
University Hospital Tübingen
Otfried-Müller-Strasse 14, 72076 Tübingen
Tel.: +49(0)7071 29-84113
Fax: +49(0)7071-29-25062
Lars.Zender@med.uni-tuebingen.de

Dr. Daniel Dauch
Comprehensive Cancer Center Tübingen-Stuttgart &
Department of Vegetative and Clinical Physiology
University Hospital Tübingen
Otfried-Müller-Strasse 14, 72076 Tübingen
Tel.: +49(0)7071 29-83180
Fax: +49(0)7071-29-25062
Daniel.dauch@med.uni-tuebingen.de