E3 Ligase Ligand-Linker Conjugates

Building a protein degrader from separate parts takes two coupling steps, one to join the E3 ligase ligand to the linker and one to attach the target protein ligand, and the first of these repeats unchanged across an entire compound series. Conjugates that arrive with the ligase ligand and the linker already joined remove that step, so a series expands by a single reaction from the warhead in hand. The terminal group carried by the conjugate then becomes the selection criterion, since it must match the functional group available on the warhead. Amerigo Scientific offers functionalized VHL, cereblon, IAP and MDM2 ligands incorporating PEG and alkyl linkers across a range of chain lengths and terminal chemistries, ready for conjugation to a target protein ligand.

VHL Ligand-Linker Conjugates

VHL-recruiting degraders are built on the AHPC hydroxyproline scaffold, of which VH 032 is the widely used derivative, and the linker is attached at a position that leaves binding to VHL intact. Chain length is the first variable a series explores, and terminal chemistry determines which coupling reaction closes the molecule. Our functionalized VHL ligands incorporate PEG linkers from PEG2 to PEG8 and a short alkyl linker, terminating in carboxylic acid, primary amine, NHS ester, azide, alkyne or tosylate groups.

Applications

• Single-step PROTAC synthesis from a warhead
• Linker length series across PEG2 to PEG8
• Click assembly through azide and alkyne termini
• Amide coupling through acid, amine and NHS ester termini

Cereblon Ligand-Linker Conjugates

Cereblon-recruiting degraders are built on thalidomide and its analogs, with the linker attached through the phthalimide ring. Ether and amide connections between the ligand and the linker give different conformational behavior and different metabolic profiles, and both are represented here alongside pomalidomide-based conjugates.

We provide functionalized cereblon ligands incorporating PEG and short alkyl linkers, connected through either an ether or an amide bond, and terminating in carboxylic acid, primary amine, protected amine, azide, propargyl, NHS ester, tert-butyl ester or tosylate groups.

Applications

• Single-step PROTAC synthesis from a warhead
• Comparison of ether and amide linkage chemistry
• Click assembly through azide and propargyl termini
• Protected amine termini for stepwise assembly

IAP and MDM2 Ligand-Linker Conjugates

CRBN and VHL are not the only ligases available to a degrader program. IAP family ligases are recruited by SNIPERs, a degrader class built on IAP-binding ligands, and MDM2 is recruited through nutlin-derived ligands that occupy its p53 binding site. Programs move to these ligases when tissue distribution, resistance, or target scope makes the two canonical options less suitable.

Our cIAP1 ligand-linker conjugates are supplied as free bases and hydrochloride salts, each ready for conjugation to a target protein ligand in SNIPER construction, together with a nutlin-based MDM2 ligand carrying a 4-unit PEG linker that terminates in an azide for click assembly onto an alkyne-bearing warhead.

Applications

• Single-step SNIPER synthesis from a warhead
• Degrader design built on IAP recruitment
• Degrader design built on MDM2 recruitment
• Click assembly through the azide terminus
• Comparison of ligase choice across a fixed warhead