Targeting the intrinsically disordered region of ERalpha to overcome antiestrogen resistance

Sex hormone receptors like estrogen receptor (ER or ESR1) and androgen receptor (AR) are critical transcriptional regulators of cancer cell proliferation through their regulation of gene expression. Their N-terminal domains (NTDs) are intrinsically disordered but have emerged as a therapeutic target due to their role in transcriptional regulation. For instance, AR-NTD inhibitors have been discovered over the past decade. Unlike the constitutively active AR-NTD, the ER-NTD requires phosphorylation at Ser118 for activation. Protein kinases like CDK7 that phosphorylate Ser118 have been targeted, with multiple CDK7 inhibitors that inhibit Ser118 phosphorylation, even in therapy-resistant ER Y537S/D538G mutants. This development highlights the significance of targeting this disordered region while revealing the toxicity risks of these CDK7 inhibitors due to their other cellular roles. Our direct targeting of the ER-NTD with small molecules represents a promising approach to repressing oncogenic ER signaling and inhibiting ER-positive breast cancer growth, especially relevant for tumor-observed ESR1 fusions lacking the hormone-binding domain or when resistance develops to anti-estrogen therapy.