Working Paper
Authors
- Christiane Kofink Boehringer Ingelheim (Austria) ,
- Nicole Trainor University of Dundee ,
- Barbara Mair Boehringer Ingelheim (Austria) ,
- Simon Wöhrle Boehringer Ingelheim (Austria) ,
- Melanie Wurm Boehringer Ingelheim (Austria) ,
- Nikolai Mischerikow Boehringer Ingelheim (Austria) ,
- Gerd Bader Boehringer Ingelheim (Austria) ,
- Klaus Rumpel Boehringer Ingelheim (Austria) ,
- Thomas Gerstberger Boehringer Ingelheim (Austria) ,
- Yunhai Cui Boehringer Ingelheim (Germany) ,
- Peter Greb Boehringer Ingelheim (Austria) ,
- Geraldine Garavel Boehringer Ingelheim (Austria) ,
- Maximilian Scharnweber Boehringer Ingelheim (Austria) ,
- Julian Fuchs Boehringer Ingelheim (Austria) ,
- Gabriela Gremel Boehringer Ingelheim (Austria) ,
- Paolo Chette Boehringer Ingelheim (Austria) ,
- Stefan Hopf Boehringer Ingelheim (Austria) ,
- Nicole Budano Boehringer Ingelheim (Austria) ,
- Jörg Rinnenthal Boehringer Ingelheim (Austria) ,
- Gerhard Gmaschitz Boehringer Ingelheim (Austria) ,
- Emelyne Diers University of Dundee ,
- Ross McLennan University of Dundee ,
- Michael Roy University of Dundee ,
- Claire Whitworth University of Dundee ,
- Vesna Vetma University of Dundee ,
- Moriz Mayer Boehringer Ingelheim (Austria) ,
- Manfred Koegl Boehringer Ingelheim (Austria) ,
- Alessio Ciulli University of Dundee ,
- Harald Weinstabl Boehringer Ingelheim (Austria) ,
- William Farnaby
University of Dundee
Abstract
Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit the target and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. The oral route of administration is the option of choice in the clinic, but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4 deficient cancers. Here we outline structure- and property-guided approaches that led to the first orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.
Content

Supplementary material

Supplementary information
Synthetic protocols, analytical data and x-ray structure data