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 dynamic conformational changes 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
  • Innovative Medicines Initiative (Joint Undertaking under grant agreement no. 875510 (EUbOPEN project))
  • UK Research and Innovation (Postdoctoral Fellowships Guarantee Scheme funding the Marie Skłodowska–Curie Actions Individual Fellowship (Council Ref. EP/Z001986/1) to A.S.)

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