Stefan Knapp

3 weeks ago | science.org | Antoine Régimbeau |Martin Kihoulou |Yubei Xiang |Nicolai D Raig |Katherine J. Surridge |Marta Sanz-Murillo | +11 more

AbstractIncreased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson’s disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have entered clinical trials. Here, to our knowledge, we present the first type II kinase inhibitors that target LRRK2. Targeting the inactive conformation of LRRK2 is functionally distinct from targeting the active-like conformation using type I inhibitors.

Feb 2, 2025 | nature.com | Susanne Müller |Stefan Knapp

AbstractThe nine human NR3 nuclear receptors translate steroid hormone signals in transcriptomic responses and operate multiple highly important processes ranging from development over reproductive tissue function to inflammatory and metabolic homeostasis. Although several NR3 ligands such as glucocorticoids are invaluable drugs, this family is only partially explored, for example, in autoimmune diseases and neurodegeneration, but may hold therapeutic potential in new areas.

Jan 9, 2025 | nature.com | Philipp Münick |Alexander Strubel |Dimitrios-Ilias Balourdas |Julianne Funk |Marcel Tuppi |Busra Yuksel | +4 more

AbstractInfection of cells with high-risk strains of the human papillomavirus (HPV) causes cancer in various types of epithelial tissue. HPV infections are responsible for ~4.5% of all cancers worldwide. Tumorigenesis is based on the inactivation of key cellular control mechanisms by the viral proteins E6 and E7. The HPV E6 protein interacts with the cellular E3 ligase E6AP, and this complex binds to the p53 DNA-binding domain, which results in degradation of p53.

Nov 25, 2024 | nature.com | Martin P. Schwalm |Johannes Dopfer |Adarsh Kumar |Francesco Greco |Nicolas Bauer |Frank Lohr | +18 more

AbstractRecent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community.

Sep 5, 2024 | nature.com | Stefan Knapp

A recent study published in Nature by Radko-Juettner and colleagues reports an unexpected mutant-specific synthetic lethality in which the E3 protein ubiquitin ligase DCAF5 specifically degrades mutant but not wild-type SWI/SNF chromatin remodeling complexes.1 DCAF5 contains a likely druggable WDR domain, providing a new avenue for the development of novel therapeutics for aggressive cancers with SMARCB1 loss of function mutations.