LCL161-O-Me

Target: This ligand targets inhibitor of apoptosis proteins cIAP1, cIAP2, and XIAP through BIR domains in biochemical or cellular target-engagement studies.

Mechanism of Action: Used as the target-protein recognition element, this ligand provides the binding interface for inhibitor of apoptosis proteins cIAP1, cIAP2, and XIAP through BIR domains. 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 inhibitor of apoptosis proteins cIAP1 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.

• LCL161-Based PROTAC Design: LCL161-O-Me can be used as a cereblon-recruiting ligand component to build PROTACs aimed at degrading CRBN-linked substrates. Researchers can explore linker length and attachment points to tune ternary complex formation, ubiquitination efficiency, and degradation kinetics, enabling systematic mapping of structure–activity relationships for targeted protein elimination.

• Cereblon-Dependent Substrate Degradation: As a CRBN-binding warhead, LCL161-O-Me supports PROTAC strategies that drive ubiquitin-proteasome–mediated turnover of target proteins. Experimental workflows may include evaluating degradation specificity across candidate substrates, quantifying dose–response and time-course effects, and confirming dependence on CRBN and proteasomal activity using genetic or pharmacologic perturbations.

• Ternary Complex Optimization Studies: LCL161-O-Me–derived PROTACs are suitable for mechanistic studies of ternary complex stability and cooperativity. By varying the PROTAC architecture while keeping the CRBN-binding element constant, investigators can assess how changes in geometry and flexibility influence target recruitment, ubiquitin transfer, and overall degradation potency in cell-based reporter or endogenous target assays.

• Versatile Linker and Targeting Modules: The ligand can be integrated into modular PROTAC platforms where different targeting moieties are swapped to redirect degradation toward diverse proteins. This enables comparative screening of target engagement versus productive ubiquitination, helping identify which target classes are most efficiently degraded and guiding rational design of next-generation chimeras with improved selectivity and efficacy.

LCL161-O-Me is an IAP ligand scaffold used for recruiting IAP E3 ligases in degrader design. It should be incorporated through a validated linker-ready analog or tolerated peripheral vector.

Structure: LCL161-O-Me is an IAP ligand containing a bicyclic thiazoline/thiophene-like aromatic region, cyclohexyl and proline-derived amide elements, and a methoxyphenyl substituent. It is conformationally constrained and rich in amide hydrogen-bonding groups.

Reactivity: This compound is an IAP-binding moiety, so in PROTAC design it functions as the E3 ligase ligand rather than the target-protein ligand. Linker extension should be directed from the tolerated O-methyl or aryl substituent vector or from a linker-ready analog, using alkyl, PEG, amide, or carbamate linkers to connect a chosen target ligand. Because the molecule lacks a free carboxylic acid or primary amine, direct coupling may require demethylated or otherwise functionalized analogs.