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Adjudication committee
- First opponent: Head of Department of Developmental Biology Ondřej Machoň, Czech Academy of Sciences, Czech Republic
- Second opponent: Associate Professor Nina Marie Pedersen, Østfold University College, Norway
- Third member and chair of the evaluation committee: Professor Marit Inngjerdingen, University of Oslo
Chair of the Defence
Associate Professor Lars Fjellbirkeland, University of Oslo
Summary
This thesis is situated within molecular pharmacology, cell signaling, and small-molecule drug development, with a focus on tankyrase inhibition in cancer and idiopathic pulmonary fibrosis (IPF).
Tankyrase 1 and 2 (TNKS) regulate WNT/β-catenin and YAP signaling. Pathogenic activation of these pathways contributes to tumor growth, immune modulation, and fibrotic tissue remodeling. The main hypothesis was that new TNKS inhibitors with improved drug-like properties could suppress these disease-driving pathways and exert antitumor and antifibrotic effects in relevant preclinical models.
To test this, the work combined medicinal chemistry, structure–activity relationship studies, crystallography, biochemical assays, cell-based reporter systems, tumor cell line screening, mouse models, primary human lung fibroblasts, 3D fibrosis models, and human precision-cut lung slices.
The studies identified tumor cell lines sensitive to TNKS inhibition and showed that treatment reduced WNT/β-catenin, YAP, PI3K/AKT, and MYC-associated signaling. Optimization of triazole-based inhibitors led to OM-153, a potent and selective TNKS inhibitor with improved pharmacokinetic properties. In mouse tumor models, OM-153 inhibited WNT/β-catenin signaling, reduced colorectal tumor growth, enhanced anti-PD-1 treatment responses in melanoma, and demonstrated a therapeutic window.
In IPF-relevant models, OM-153 stabilized AXIN1 and AMOTL1, suppressed WNT/β-catenin and YAP signaling, and reduced profibrotic extracellular matrix gene expression and deposition across in vitro, in vivo, and human ex vivo systems. The thesis also explored an alternative nicotinamide-site inhibitor strategy to improve TNKS selectivity.
Overall, these findings support TNKS inhibition as a mechanistically distinct therapeutic approach with translational potential in selected cancers and pulmonary fibrosis, and provide a foundation for continued preclinical development of TNKS inhibitors.
Additional information
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