Project Details
Projekt
Inhibierung von HECT-Ligasen zur Krebstherapie
Subject Area
Hematology, Oncology
Pharmacology
Structural Biology
Cell Biology
Pharmacology
Structural Biology
Cell Biology
Term
from 2018 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 267467939
Ubiquitination enzymes regulate countless physiological and disease-associated processes and have emerged as powerful targets on the drug discovery arena. Ubiquitin ligases (E3 enzymes) are particularly interesting points of therapeutic intervention. With an estimated 1000 members in the human proteome, the E3 family is the most diversified among the different classes of ubiquitination enzymes and mediates the recruitment of substrates for modification, thus providing key specificity determinants in ubiquitin signaling. HECT-type E3 enzymes contain a defined catalytic center and have historically been expected to be ‘druggable’. Surprisingly, however, few small-molecule discovery efforts targeting HECT E3 enzymes have been reported, despite crucial roles of these enzymes in human pathogeneses, including various types of cancer.During the first funding period of the Research Group Martin Eilers, Nikita Popov, and colleagues discovered that downregulation of the HECT E3 enzyme HUWE1 presents a therapeutic window in colorectal carcinoma. This work has also led to the identification of specific small-molecule inhibitors by high-throughput screening. Intriguingly, the identified compounds were found to block MYC-dependent transcriptional activation in colorectal cancer cells, but not in stem and normal colon epithelial cells. These selective effects could be pinpointed to the stabilization of a particular substrate of HUWE1, the transcription factor MIZ1, that can form repressive complexes with MYC. Building on these proof-of-principle results, we aim to uncover the molecular basis of the identified inhibitors, utilize this knowledge for the development of optimized compounds, and subject them to in vivo analyses. These studies will go hand-in-hand with a systematic interrogation of the precise roles of HUWE1 during homeostasis and tumor maintenance – a vital prerequisite for exploiting the activity of this ligase therapeutically. To accomplish this research plan we will bundle our structural (Sonja Lorenz), medicinal-chemical (Stefan Laufer), and cell biological (Nikita Popov) expertise. Additional synergies will arise from interactions with other members of the Research Group, particularly Martin Eilers (biology of HUWE1 in MYC-mediated transcriptional regulation), Lars Zender (mosaic mouse models), Armin Wiegering (patient-derived organoids), Antti Poso (docking), and Andreas Rosenwald (histopathology service). We are therefore in an excellent position to define the therapeutic window that HUWE1 presents in cancer therapy, thereby providing unprecedented evidence for the accessibility of HECT E3 enzymes to specific small-molecule inhibition in vivo.
DFG Programme
Research Units
