Co-repressor of Repressor Element-1 Silencing Transcription complex (CoREST) (CoREST)

The Co-repressor of Repressor Element-1 Silencing Transcription (CoREST) complex is an epigenetic regulatory assembly that includes histone deacetylase 1 (HDAC1) and the scaffold protein RCOR1. It plays a critical role in gene silencing by modifying chromatin structure through histone deacetylation. In the context of oncology, the CoREST complex has been identified as a synthetic lethal target for cancers harboring loss-of-function mutations in the STK11 (LKB1) tumor suppressor gene. Inhibition of the CoREST complex, specifically the HDAC1-containing form, reverses the immune evasion phenotype associated with STK11 deficiency by promoting the expression of immunomodulatory genes and increasing T-cell infiltration into the tumor microenvironment. Drugs like TNG260 are designed to selectively inhibit this complex to sensitize STK11-mutant tumors to immune checkpoint inhibitors such as anti-PD-1 antibodies.

Other names

RCOR1 complexHDAC1-CoREST complexTarget 3 (Tango Therapeutics)REST corepressor 1 complex

Selective inhibition of the HDAC1-containing CoREST complex, which leads to the accumulation of acetylated histones, chromatin remodeling, and transcriptional reprogramming. This process reverses the immune evasion phenotype in STK11-deficient cancer cells by upregulating immunomodulatory genes and promoting the recruitment of effector T cells, thereby sensitizing the tumor to immune checkpoint inhibitors.