N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,5,7-trimethyl-1H-indole-2-carboxamide

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Cat Number

API-0009

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Molecular Formula

C25H24N4O4

Molecular Weight

444.48

General Description

N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,5,7-trimethyl-1H-indole-2-carboxamide is a new monofunctional molecular glue compound bearing an indole with a glutarimide moiety acting as a Cereblon ligand. It was discovered through an affinity-selection mass spectrometry (ASMS) pipeline to screen for compounds that glue the E3 ubiquitin ligase CRBN to the leukemia-associated kinase LCK.

Mechanism of Action

N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,5,7-trimethyl-1H-indole-2-carboxamide mechanism of action involves the induction and stabilization of a CRBN-LCK ternary complex, leading to polyubiquitination and proteasomal degradation of LCK.

Application

N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,5,7-trimethyl-1H-indole-2-carboxamide has potential utility in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and other LCK-dependent cancers.

Hu M et al. reported a “direct-to-biology” pipeline to identify molecular glues from >20,000 crude reaction mixtures by monitoring ternary-complex dissociation kinetics with affinity-selection mass spectrometry (ASMS). After demonstrating the concept with previously reported glues for CRBN-GSPT1 and cyclophilin-KRAS, the authors generated a 4,435-member library of glutarimide-containing fragments and screened it against the leukemia-relevant pair CRBN-LCK.
Compound 17 (N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,5,7-trimethyl-1H-indole-2-carboxamide), an indole-bearing CRBN ligand, was the flagship hit. It reproducibly enriched 2.3-fold in ASMS only when both CRBN and LCK were present, which is indicative of selective ternary-complex stabilization. Resynthesized pure compound 17 displayed double-digit nM potency in AlphaScreen proximity assays and robustly degraded LCK in live-cell HiBit and immunoblot experiments. Glutarimide methylation abolished both proximity induction and degradation, confirming on-mechanism activity.

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