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CoREST1 degrader
- Development stage
- Preclinical
- Lead developer
- AstraZeneca
- Modality
- Molecular Glues → Targeted Protein Degraders (TPDs) → Small Molecules
- Administration
- Oral
01
Overview
CoREST1 degrader is an investigational small-molecule molecular glue degrader (KMGD) being developed by Iricor Therapeutics and its spin-off RejuvenRx for the treatment of oncology (including myeloproliferative neoplasms) and age-related conditions (such as thymic involution). Co-discovered by researchers at the Université de Montréal's Institute for Research in Immunology and Cancer (IRIC), the compound builds on the biology of UM171, a first-generation ex vivo CoREST degrader. Unlike UM171, this next-generation class of CoREST1 degraders is designed to be orally bioavailable for systemic in vivo administration. Mechanistically, the drug acts as a molecular glue that co-opts the CUL3-RING E3 ubiquitin ligase adapter KBTBD4 and HDAC1/2 to induce the neomorphic ubiquitination and proteasomal degradation of the REST corepressor 1 (RCOR1/CoREST1) complex. This targeted degradation dismantles the LSD1-CoREST-HDAC (LCH) transcriptional repressor complex, leading to chromatin remodeling, altered transcriptional programs, and the rejuvenation of hematopoietic stem cells.
- Other names
- CoREST molecular glue degraderKMGD
02
Targets
HDAC1 (Histone Deacetylase 1)HDAC2 (Histone deacetylase 2)KBTBD4 (Kelch repeat and BTB domain-containing protein 4)KDM1A (LSD1)RCOR1 (CoREST Complex)
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