Rational Design of PROTAC Linkers Featuring Ferrocene as a Molecular Hinge to Enable Dynamic Conformational Changes

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Abstract
Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that induce ubiquitination and degradation of a target protein via recruitment to an E3 ligase. The linker influences many steps of the PROTAC mode of action, from cellular permeability to ternary complex formation and target degradation. Much interest has therefore been devoted to linker design to fine-tune molecular and mechanistic properties of PROTACs. In this study, we present FerroTACs, a novel PROTAC design strategy incorporating ferrocene as the linker chemotype. We exemplify the approach across three different PROTAC systems: VHL-VHL (homo-PROTACs), VHL-CRBN, and VHL-BETs. We find that ferrocene's unique organometallic structure, featuring freely rotating cyclopentadienyl rings around a central Fe(II) ion, acts as a molecular hinge enabling structural adjustment to the environment that results in properties alteration, i.e., chameleonicity. Conformational analyses via NMR spectroscopy support ferrocene's role in fostering intramolecular interactions that result in a more folded state in an apolar environment. This property promotes compact conformations, improving cellular permeability and reducing efflux liabilities. Cellular assays demonstrate that FerroTACs exhibit robust target degradation and cell permeability profiles, en-par or enhanced compared to benchmark PROTACs CM11, 14a, and MZ1. These findings highlight ferrocene's potential as a new linker design strategy, offering a versatile platform to install and control molecular chameleonicity into next-generation PROTACs.
Funding Information
  • Engineering and Physical Sciences Research Council (EP/Z001986/1)
  • Vetenskapsr?det (2024-00197)
  • Ministero dell?Istruzione, dell?Universit? e della Ricerca
  • McGill University
  • Kungliga Tekniska H?gskolan
  • Diamond Light Source
  • H2020 Marie Sklodowska-Curie Actions (10102683)
  • Stiftelsen f?r?Strategisk Forskning
  • Innovative Health Initiative (875510)
  • European Federation of Pharmaceutical Industries and Associations
  • OICR

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