E3 Ligase Ligands and Target Protein Warheads

A protein degrader is assembled from three parts, and the two ends decide what the molecule does: the ligand at one end determines which E3 ligase is recruited, and the warhead at the other determines which protein is brought to it. Both ends face the same design constraint, in that the linker is attached at a position that leaves the binding surface intact, so affinity alone is an incomplete specification for either component. Amerigo Scientific provides E3 ligase ligands and target protein warheads that already carry a functional handle at a position known not to significantly affect binding, ready for conjugation to a linker.

E3 Ligase Ligands

The ligase end of a degrader determines which ubiquitination machinery performs the reaction, and the great majority of published degraders recruit either VHL or cereblon (CRBN). Thalidomide and its analogs serve as the cereblon ligands, VH 032 and related compounds as the VHL ligands, and IAP-binding compounds open a third route in which an IAP family ligase carries out the ubiquitination. Each ligand is supplied with a handle chosen so that conjugation proceeds without disrupting the ligand-ligase interface.

We provide VHL ligands carrying a primary amine handle, CRBN ligands carrying a carboxylic acid handle, and a fluorinated thalidomide in which the aromatic fluorine acts as a leaving group for direct substitution by an amine-bearing linker. IAP binding moieties are also available for degraders built on IAP recruitment.

Features

• Handle positioned to preserve ligase binding
• Amine, carboxylic acid and aryl fluoride handles
• VHL, CRBN and IAP recruitment covered
• Ready for conjugation to a linker

Target Protein Warheads

The warhead end is usually derived from an established inhibitor or ligand for the target protein. Converting such a compound into a degrader component requires an exit vector that points away from the binding pocket, together with a functional group at that position through which the linker can be attached. Warheads supplied for degrader work already carry that group, which removes the medicinal chemistry step of identifying and installing a tolerated attachment point.

We provide warheads spanning kinase, bromodomain and nuclear receptor targets, including a CDK9 antagonist, an ABL binding moiety, a BRD9 binding moiety, and a retinoic acid receptor ligand bearing an aldehyde handle for reductive amination.