N-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-ethyl-1H-indole-2-carboxamide

Inquiry

Cat Number

API-0012

If you have any other questions, please contact our experts.

Product Detail Description Scientific Support Customer Q&A

Molecular Formula

C24H22N4O4

Molecular Weight

430.46

General Description

N-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-ethyl-1H-indole-2-carboxamide is a potent monofunctional molecular glue which consists of an inverted benzothiazole extension appended to a glutarimide-based Cereblon ligand. It is a leading quality chemical tool for protein degradation which can be rapidly identified from crude unpurified reaction mixtures.

Mechanism of Action

N-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-ethyl-1H-indole-2-carboxamide acts as a thermodynamic sink to stabilize CRBN binding of the neosubstrate LCK. It was discovered to promote near-complete ubiquitination and subsequent degradation of LCK within 2 hours. The mechanism is dependent on the glutarimide moiety as N-methylation of this subunit ablates degradation activity.

Application

N-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-ethyl-1H-indole-2-carboxamide is a potential therapeutic for T-cell acute lymphoblastic leukemia (T-ALL) and other LCK-driven malignancies, including those driven by drug resistance.

Among >4,400 crude glutarimide derivatives screened against the leukemia target LCK, compound 20 (N-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-ethyl-1H-indole-2-carboxamide) exhibited the strongest ASMS enrichment strictly when both CRBN and LCK were present, indicating exceptional ternary stability. Re-synthesized pure compound 20 achieved single-digit nanomolar proximity induction, the most potent within the series, and drove near-complete LCK degradation in T-ALL cells within 2 h. Competition experiments showed it remains enriched even when 100 equiv of a weak CRBN binder is added, confirming its role as a thermodynamic sink. The benzothiazole vector, unique to compound 20, correlates with enhanced residence time and cellular efficacy, offering a clear optimization handle.

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.

Is N-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-ethyl-1H-indole-2-carboxamide selective for LCK?

Yes, research confirmed its selectivity for LCK.

What is the role of the benzothiazole group?

It increases residence time and cellular potency, a clear handle for optimization.

How does it compare to other CRBN-LCK glues?

Superior in potency, selectivity, and with faster cellular degradation kinetics.