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

Inquiry

Cat Number

API-0011

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

Product Detail Description Scientific Support Customer Q&A

Molecular Formula

C22H16ClFN4O4

Molecular Weight

454.84

General Description

3-Chloro-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-fluoro-1H-indole-2-carboxamide is a monofunctional molecular glue compound composed of a chloro-indole scaffold linked to a glutarimide core. The compound displays enhanced selectivity and Cereblon (CRBN) binding-mediated stabilization of CRBN-LCK interaction.

Mechanism of Action

By allosteric induction and stabilization of a ternary CRBN-LCK complex, 3-Chloro-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-fluoro-1H-indole-2-carboxamide promotes polyubiquitination and proteasomal degradation of the LCK protein. The functional selectivity is absolute, with exclusive neosubstrate fidelity toward LCK, and total loss of neosubstrate enrichment when other proteins are substituted.

Application

3-Chloro-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-fluoro-1H-indole-2-carboxamide has significant potential as a therapeutic agent in the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and other LCK-dependent malignancies. The rapid on-cell activity of the compound also presents it as an excellent candidate for cancer treatment, especially in cases of acquired drug resistance.

Hu M et al. mined >20,000 unpurified nanoscale reactions by ASMS, ranking candidates for slow KOFF from the CRBN-LCK ternary complex. Compound 19 (3-Chloro-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5-fluoro-1H-indole-2-carboxamide), a chloro-indole derivative appended to a glutarimide core, surfaced as the most selective glue. Its MS signal rose 2.8-fold only when both proteins were present, the highest enrichment among the hits series. Re-synthesized pure compound 19 drives proximity with sub-20 nM potency, degrades endogenous LCK in T-ALL cells within 3 h, and maintains activity under 0.5 µM competitor ligands, a durability unmatched by analogs. Cryogenic transfer immunoblots reveal exclusive ubiquitination of LCK, while GSPT1 substitution completely abolishes ASMS enrichment, underscoring the neosubstrate fidelity.

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 CRBN?

CRBN (Cereblon) is an E3 ubiquitin ligase for targeted protein degradation platforms.

What is the mechanism of action of N-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3-ethyl-1H-indole-2-carboxamide?

It stabilizes the CRBN-LCK ternary complex which results in ubiquitination and proteasomal degradation of LCK.

Does this compound degrade LCK in cells?

Yes, it degrades endogenous LCK in T-ALL cells effectively.

Is it selective for LCK?

Yes, it has exclusive fidelity for LCK.