Nuclear receptor coactivator 3 (SRC-3) (SRC-3)

Nuclear receptor coactivator 3 (SRC-3), also known as NCOA3 or AIB1, is a potent transcriptional coactivator that facilitates the activity of nuclear receptors and various other transcription factors like NF-κB and AP-1 (UniProt P48523). In the specific context of regulatory T cells (Tregs), SRC-3 acts as a master regulator of their immunosuppressive program; its genetic deletion or pharmacological inhibition leads to the loss of Treg-mediated suppression and subsequent tumor eradication in animal models (Song et al., 2021, PNAS). This target is highly significant in oncology because SRC-3 inhibition selectively "reprograms" intratumoral Tregs into effector-like cells that produce pro-inflammatory cytokines such as IFN-gamma, thereby breaking tumor immune tolerance (Liu et al., 2019, Scientific Reports). Small molecule inhibitors like SI-2 have been developed to target the SRC-3 interaction interface, demonstrating high efficacy in reducing tumor burden without inducing systemic autoimmunity in preclinical studies (Lonard and O'Malley, 2012, Molecular Cell). Beyond its role in Tregs, SRC-3 is frequently overexpressed in various cancers, including breast and prostate, where it drives cell proliferation, survival, and metastasis (PubMed: 28539265).

Other names

NCOA3AIB1Amplified in breast cancer 1ACTRRAC3TRAM-1p/CIPSteroid receptor coactivator 3

Small molecule inhibition of SRC-3 disrupts its recruitment to target gene promoters in regulatory T cells (Tregs), resulting in the downregulation of immunosuppressive genes and the upregulation of pro-inflammatory cytokines like IFN-gamma, which enhances anti-tumor immunity (Song et al., 2021, PNAS).