CH 55

Target: This ligand targets retinoic acid receptors RARα, RARβ, and RARγ in biochemical or cellular target-engagement studies.

Mechanism of Action: Used as the target-protein recognition element, this ligand provides the binding interface for retinoic acid receptors RARα, RARβ, and RARγ. In PROTAC design, a derivatizable position on the ligand can be connected through an optimized linker to an E3 ligase ligand, such as a CRBN, VHL, or IAP recruiter, while preserving productive target engagement. The resulting bifunctional molecule brings retinoic acid receptors RARα into proximity with the recruited E3 ligase, enabling ternary-complex formation. If the complex has favorable geometry and residence time, target lysine ubiquitination is promoted, leading to proteasome-dependent degradation in experimental systems.

• PROTAC-Mediated Degradation Studies: CH 55 can be used as a ligand component in PROTAC designs to probe targeted degradation of its cognate protein. Researchers can evaluate ternary complex formation, ubiquitination efficiency, and degradation kinetics in relevant cell models to establish whether CH 55 enables efficient proteasome-dependent removal.

• Target Engagement and Kinetics: Incorporating CH 55 into PROTAC constructs supports quantitative studies of target engagement and time-dependent loss of protein levels. By comparing degradation profiles across linker lengths and PROTAC concentrations, investigators can map the relationship between binding potency, ternary complex stability, and degradation rate.

• Ubiquitin-Proteasome Pathway Validation: CH 55-based PROTACs are suitable for mechanistic validation of degradation via the ubiquitin-proteasome system. Experiments using proteasome inhibition and ubiquitination perturbations can confirm that CH 55-driven recruitment leads to ubiquitin conjugation and subsequent proteasomal turnover of the target protein.

• Selectivity Profiling in Cells: CH 55-containing PROTACs can be applied to assess degradation selectivity across related proteins. By performing proteome-wide or targeted immunoblot panels after PROTAC treatment, researchers can determine whether CH 55 confers preferential degradation of the intended target while minimizing off-target destabilization.

• Structure-Activity Optimization: CH 55 can serve as a starting ligand for rational PROTAC optimization. Systematic variation of linker chemistry and attachment points can be used to improve ternary complex formation and degradation potency, enabling researchers to identify structural features that maximize target degradation while maintaining cellular activity.

CH 55 is a retinoid receptor/CRABP ligand intended for use as the target-engaging component or reference ligand in PROTAC discovery workflows. Its known small-molecule recognition profile enables rational linker-vector evaluation and comparative degrader design. This molecule is described in detail below.

Structure: The structure of CH 55 is characterized by carboxylic acid or carboxylate handle. These features provide defined hydrogen-bonding, hydrophobic, and steric elements that can support affinity retention while enabling analogue-based linker-vector selection.

Reactivity: The acid handle supports amide coupling with amino-PEG, alkyl-diamine, piperazine, or aminoalkyl E3-ligase ligands. For PROTAC construction, the POI ligand can be paired with CRBN ligands such as thalidomide, pomalidomide, or lenalidomide analogues, VHL ligands such as VH032 derivatives, or less common IAP/MDM2/cIAP-recruiting ligands, with alkyl, PEG, piperazine, triazole, or amide linkers screened for ternary-complex formation. In practice, incorporation into PROTACs should begin from derivatives that preserve the reported binding pharmacophore, followed by systematic variation of linker length, polarity, rigidity, and exit-vector geometry to optimize target engagement, E3 recruitment, and cellular degradation readouts.