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

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Cat Number

API-0013

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Product Detail Description Scientific Support Customer Q&A

Molecular Formula

C23H20N4O4

Molecular Weight

416.43

General Description

N-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-methyl-1H-indole-2-carboxamide is a professional monofunctional molecular glue capable of stabilizing the interaction between E3 ubiquitin ligase Cereblon and the kinase LCK. It is distinguished by a cyclohexyl-methoxy tail linked to an indole-glutarimide scaffold, which confers moderate lipophilicity and a unique binding signature.

Mechanism of Action

N-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-methyl-1H-indole-2-carboxamide exerts its effect by promoting a stable, ternary-complex-dependent interaction between CRBN and LCK, thereby functioning as a thermodynamic sink to facilitate the polyubiquitination and proteasomal degradation of LCK.

Application

N-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-methyl-1H-indole-2-carboxamide has considerable potential as a therapeutic agent for refractory T-ALL, especially in instances where resistance to conventional inhibitors has emerged.

Hu M, et al. identified compound 21 (N-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-methyl-1H-indole-2-carboxamide) as part of their ASMS-driven screen for CRBN-LCK molecular glues from >20 000 crude reaction mixtures. This analog features a novel cyclohexyl-methoxy tail that imparts modest lipophilicity as well as a unique binding signature.
The observed signal is purely ternary-complex-dependent and is abolished when LCK is swapped for GSPT1 or when the glutarimide is N-methylated (analogue 22), consistent with orthosteric binding. Competition assays demonstrate that it is resistant to 50 equiv of a weak binder to CRBN, consistent with formation of a stable thermodynamic sink, and crystallographic predictions of the co-crystal structure place the cyclohexyl group into a hydrophobic groove between the two proteins, accounting for selectivity.

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 are CRBN-LCK molecular glues?

They promote and stabilize a ternary complex of CRBN and the LCK kinase, resulting in LCK degradation.

What is the key structural feature of N-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-methyl-1H-indole-2-carboxamide?

It has an indole-glutarimide core linked to a novel cyclohexyl-methoxy tail.

How does this compound compare to other CRBN glues?

It is a unique chemotype with activity in resistant settings.