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meta-Directing Deactivators: –NO2, –CN, –CHO, –⁠CO2R, –COR, –CO2H01:13

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All meta-directing substituents are deactivating groups. These substituents withdraw electrons from the aromatic ring, making the ring less reactive toward electrophilic substitution. For example, the nitration of nitrobenzene is 100,000 times slower than that of benzene because of the deactivating effect of the nitro group. The first step in an electrophilic aromatic substitution is the addition of an electrophile to form a resonance-stabilized carbocation. The energy diagrams for...
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If a set of reactants can yield multiple constitutional isomers, but one of the isomers is obtained as the major product, the reaction is said to be regioselective. In such reactions, bond formation or breaking is favored at one reaction site over others.
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A significant aspect of hydroboration–oxidation is the regio- and stereochemical outcome of the reaction.
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The concept of prochirality leads to the nomenclature of the individual faces of a molecule and plays a crucial role in the enantioselective reaction. It is a concept where two or more achiral molecules react to produce chiral products. A typical process is the reaction of an achiral ketone to generate a chiral alcohol. Here, the achiral reactant reacts with an achiral reducing agent, sodium borohydride, to generate an equimolar mixture of the chiral enantiomers of the product. For example, an...
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A Degron Blocking Strategy Towards Improved CRL4CRBN Recruiting PROTAC Selectivity.

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Summary

Developing targeted protein degraders requires high selectivity. This study modified molecular glues to remove unwanted degradation, enhancing PROTAC selectivity without hindering target engagement, offering new tools for drug development.

Keywords:
CereblonIMiDsNeo-substratesPROTACsTargeted protein degradation

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Medicinal Chemistry

Background:

  • Small molecules that induce protein degradation are crucial pharmacological tools and emerging clinical agents.
  • Achieving selectivity in these molecules is a significant challenge for their full potential.
  • CRL4CRBN-recruiting PROteolysis TArgeting Chimeras (PROTACs) often exhibit intrinsic monovalent degradation via neo-substrate recruitment.

Purpose of the Study:

  • To address the selectivity challenge in CRL4CRBN-recruiting PROTAC design.
  • To attenuate or remove the monovalent degradation function of known CRL4CRBN molecular glues.
  • To generate a PROTAC with an improved selectivity profile by applying novel design principles.

Main Methods:

  • Leveraged structural insights of CRL4CRBN neo-substrates.
  • Modified known CRL4CRBN molecular glues (CC-885, Pomalidomide) to block neo-substrate binding.
  • Applied design principles to a BRD9 PROTAC (dBRD9-A) to create a selective analogue.
  • Utilized computational modeling to assess ternary complex formation.

Main Results:

  • Successfully attenuated and removed monovalent degradation functions from CC-885 and Pomalidomide.
  • Generated a BRD9 PROTAC analogue with a demonstrably improved selectivity profile.
  • Computational modeling confirmed that the degron-blocking design does not impede PROTAC-induced ternary complex formation.

Conclusions:

  • The presented design principles offer a strategy to enhance PROTAC selectivity by mitigating off-target degradation.
  • The developed tools and methodologies can aid in the design of more selective targeted protein degraders.
  • This work contributes to advancing the field of targeted protein degradation for therapeutic applications.