3-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H-indole-2-carboxamide

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Cat Number

API-0010

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Product Detail Description Scientific Support Customer Q&A

Molecular Formula

C22H17BrN4O4

Molecular Weight

480.04

General Description

3-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H-indole-2-carboxamide is a professional monofunctional molecular glue scaffold. It is composed of a 3-bromo-indole moiety conjugated to a glutarimide-based Cereblon ligand. This compound selectively stabilizes the neo-protein-protein interaction between E3 ubiquitin ligase CRBN and kinase LCK. It has a high degree of selectivity and exhibits superior cellular potency, as indicated by robust signal enrichment in ternary complex assay.

Mechanism of Action

3-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H-indole-2-carboxamide is a thermodynamic sink that stabilizes the LCK-glue-CRBN ternary complex and enables proximity-induced polyubiquitination and proteasomal degradation of LCK.

Application

As a potent CRBN-mediated LCK degrader with nanomolar proximity induction, 3-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H-indole-2-carboxamide has potential for therapeutic use in T-cell acute lymphoblastic leukemia (T-ALL) and other LCK-dependent cancers.

Among the CRBN-LCK molecular glues unveiled by ASMS-driven direct-to-biology platform, compound 18 (3-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1H-indole-2-carboxamide) stands out for its superior residence time and cellular efficacy. This indole-substituted glutarimide was plucked from a 4 435-member crude library because its signal intensified 2.1-fold only when both CRBN and LCK were present, a selectivity echoed in subsequent orthogonal tests.
Purified compound 18 triggers nanomolar proximity in AlphaScreen, collapses LCK levels in HiBit assays within 4 h, and maintains full activity even when 100 equiv of a non-glutarimide CRBN binder compete for the receptor, illustrating its dominance as a thermodynamic sink. Replacement of LCK by GSPT1 abolishes enrichment, proving neosubstrate specificity, while N-methylation of glutarimide erases both recruitment and degradation, confirming the glue mechanism.

Fig. 1 Five candidate molecular glues showed affinity enrichment. (Hu M.; et al. 2025)

References

Hu M, et al. Direct-to-Biology Enabled Molecular Glue Discovery. Journal of the American Chemical Society, 2025.

What is the AlphaScreen activity of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,5,7-trimethyl-1H-indole-2-carboxamide?

It shows nanomolar AlphaScreen proximity activity.

How was this molecular glue identified?

It was discovered using an affinity-selection mass spectrometry (ASMS) platform.

Does this molecular glue lead to LCK degradation?

Yes, it rapidly degrades LCK within 4 hours in cellular HiBit assays.

Why is this molecular glue amenable to drug optimization?

The indole-based scaffold allows for easy medicinal chemistry manipulation.