PROTACs & Molecular Glues - SYNthesis med chem

Targeted protein degradation (TPD) represents a new modality in drug discovery where the protein of interest (POI) target is degraded via the cellular proteosome system.

Compared to traditional small molecule inhibition, TPD offers a new mode of action to interrogate high value “undruggable” targets and also the possibility of an extended therapeutic window

At SYNthesis med chem, we have an experienced team that can provide a full suite of capabilities for TPD discovery. Since 2018, we have provided synthetic chemistry and medicinal chemistry design support for clients in both FTE and FFS project modes. For our FTE clients, we have contributed significantly to building libraries of PROTAC degraders and advancing dedicated TPD programs. Together with our partner Viva Biotech, we can offer a fully integrated platform that includes degrader hit screening, CADD, TPD biology and DMPK services.

PROTAC Degrader Building Block Collection

High quality curated library of synthesis-ready building blocks to accelerate TPD discovery and development. Our in-stock collection of PROTAC building blocks contains >500 compounds:

Selection of E3 ligase binders (CRBN, VHL, IAP, MDM2, etc)
E3 ligase negative controls
Diverse library of linker lengths (short/medium/long)
Linkers with diversity of composition (simple carbon/PEG, rigid/ flexible, tunable basic centers, sp3-rich, spirocycles, focus on druglike linker motifs for improved properties)
Range of linker attachment functionality (alcohols, aldehydes, alkyl amines, alkyl halides, alkynes, anilines, aryl halides, azides, boronic acids/esters, carbamates, carboxylic acids/esters, ketones, phenols, thiols, etc)
Pre-assembled partial PROTAC probes for rapid library generation
Proof-of-concept acceleration kits
Compounds available in mg to multi-gram quantities
Continuous literature monitoring to include next generation E3 binders and linkers
Well established PROTAC synthesis and purification protocols

E3 Ligase Binder Diversity

Coverage of common E3 ligase binding motifs (CRBN, VHL, IAP, MDM2) plus underexplored E3 ligases
Next generation E3 binding motifs with improved properties (eg phenyl glutarimides (PG) and achiral phenyl dihydrouracil (PDHU) motifs to recruit CRBN)

TPD Building blocks Catalogue

Broad range of linkers available with variation of length, rigidity flexibility, composition (sp3-rich, spirocycles, etc).
Focus on more druglike linker motifs to provide improved properties
Incorporation into pre-assembled linker + E3 binder partial probes

Proof-of-Concept Acceleration Kits

Quickly establish POC and optimal linker length range for new TPD programs
Set of partial probes ready for attachment to your POI binder of choice
Available in 25 mg quantities
Corresponding E3 ligase negative control partial probes available on request

Fully Integrated Platform Services

Together with Viva Biotech, we can provide a one-stop shop for TPD-based programs.

Protein Production & Structural Biology

>100 PROTAC ternary structures determined (X-Ray and cryo-EM)

Screening Platform

binding/ternary complex characterization
200K diversity library, 2K fragment library
ASMS screening technology to identify new binders, molecular glue discovery

Bioassays

target enzymatic activity assays (ADP-Glo/Kinase, TR-FRET, PhosphoSens)
target binding binary assays (FP, tracer displacement, SPR, in cell nanoBRET TE)
ternary assays (PPI HTRF, AlphaLISA, competition assays, in cell nanBIT PPI)
degradation assays (WB, FACS, in-cell ELISA, HTRF/ AlphaLISA)
cell survival and functional assays (cell proliferation, phosphorylation, HTRF, AlphaLISA, WB, Apoptosis)