AbstractThe probing of small molecules with heterocyclic scaffolds covering unexplored chemical space and the evaluation of their biological relevance are essential parts of forward chemical genetics approaches and for the development of potential small‐molecule therapeutics. In this study, we profiled sets of chromenopyrazoles (CMPs) and tetrahydroquinolines (THQs), originally developed to target the protein–RNA interaction of LIN28–let‐7, in a cell painting assay (CPA) measuring cellular morphological changes. Selected LIN28‐inactive CMPs and THQs induced cellular morphological changes to different extents. The most CPA‐active CMPs 2 and 3 exhibited high bio‐similarity with the LCH and BET clusters, while the most CPA‐active THQs 13 and 20 indicated a mechanism of action beyond the currently established biosimilarity clusters. Overall, this work demonstrated that CPA is useful in revealing “hidden” biological targets and mechanisms of action for biologically inactive small molecules, which are CMPs and THQs targeting the RNA‐binding protein LIN28 in this case, evaluated in target‐based strategies. When compared with annotated reference compounds, CMP 3 exhibited a high biosimilarity with the dual BRD7/9 degrading PROTAC VZ185, suggesting that CPA could potentially function as a new phenotypic approach to identify degrader molecules.

01 Dec 2023·ChemBioChem

A Degron Blocking Strategy Towards Improved CRL4^CRBN Recruiting PROTAC Selectivity**

Article

Author: Roumeliotis, Theodoros I ; Wah Hak, Laura Chan ; van Montfort, Rob L M ; McAndrew, P Craig ; Mitsopoulos, Costas ; Collins, Ian ; Sialana, Fernando J ; Warne, Justin ; Chopra, Rajesh ; Hahner, Tamas ; Cabry, Marc P ; Le Bihan, Yann-Vaï ; Caldwell, John J ; O'Hanlon, Jack A ; Pierrat, Olivier A ; Choudhari, Jyoti ; Wang, Hannah Z ; Bouguenina, Habib ; Scarpino, Andrea ; Burke, Rosemary ; Stubbs, Mark ; Sadok, Amine

AbstractSmall molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents. However, to fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed the issue of selectivity in the design of CRL4CRBN recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used to generate CRL4CRBN recruiting PROTACs have well described intrinsic monovalent degradation profiles by inducing the recruitment of neo‐substrates, such as GSPT1, Ikaros and Aiolos. We leveraged structural insights from known CRL4CRBN neo‐substrates to attenuate and indeed remove this monovalent degradation function in well‐known CRL4CRBN molecular glues degraders, namely CC‐885 and Pomalidomide. We then applied these design principles on a previously published BRD9 PROTAC (dBRD9‐A) and generated an analogue with improved selectivity profile. Finally, we implemented a computational modelling pipeline to show that our degron blocking design does not impact PROTAC‐induced ternary complex formation. We believe that the tools and principles presented in this work will be valuable to support the development of targeted protein degradation.

24 Jan 2019·Journal of Medicinal ChemistryQ1 · MEDICINE

Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel–Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7

Q1 · MEDICINE

Article

Author: Zoppi, Vittoria ; Ciulli, Alessio ; Hughes, Scott J. ; Gmaschitz, Teresa ; Daniels, Danette L. ; Spallarossa, Andrea ; Wieshofer, Corinna ; Koegl, Manfred ; Riching, Kristin M. ; Testa, Andrea ; Maniaci, Chiara

Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be a lengthy and unpredictable process, and it remains unclear whether any combination of E3 and target might be productive for degradation. We describe a probe-quality degrader for a ligase-target pair deemed unsuitable: the von Hippel-Lindau (VHL) and BRD9, a bromodomain-containing subunit of the SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could be optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns and linkers and monitoring cellular degradation activities, kinetic profiles, and ubiquitination, as well as ternary complex formation thermodynamics. The emerged structure-activity relationships guided the discovery of VZ185, a potent, fast, and selective degrader of BRD9 and of its close homolog BRD7. Our findings qualify a new chemical tool for BRD7/9 knockdown and provide a roadmap for PROTAC development against seemingly incompatible target-ligase combinations.

100 Deals associated with VZ-185

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	Italy	University of Genova	12 Dec 2018
Neoplasms	Preclinical	United Kingdom	University Of Dundee	12 Dec 2018
Neoplasms	Preclinical	Austria	Boehringer Ingelheim RCV GmbH & Co. KG	12 Dec 2018

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