Identification of novel estrogen receptor inhibitors for the treatment of hormone resistant breast cancer

Estrogen receptor alpha positive (ERα+) disease constitutes approximately 75% of all breast cancer (BCa) cases. However resistance to hormone therapy is observed in early-stage as well as in metastatic disease. Importantly, 70% of ERα+ primary tumors retain active ERα when they metastasize and, therefore, ERα continues to play a role in the resistant form of the disease. Moreover, the effectiveness of conventional hormone therapies is hampered due to gain-of-function mutations that may render the receptor constitutively active. Thus drugs that target the ERα estrogen binding site can become ineffective with time. Moreover, cross-talk between ERα and activated growth factor receptors, or their downstream kinases have shown to play a major role in activating ERα even in the absence of estradiol. Taken together, these observations highlight the importance of developing therapeutics that target alternative sites on the receptor, for instance, those that directly act on the co-activator binding pocket called activation function-2 (AF2) site. Using methods of in-silico screening followed by a systematic computer-guided lead optimization process, we were able to develop several promising small-molecule inhibitors that target the AF2 functional site of ERs. This thesis describes the establishment of an experimental pipeline and development of such inhibitors. The identified lead compound VPC-16606 effectively blocked ERα-co-activator interactions, demonstrated a strong anti-proliferative effect against a panel of ERα+ cells including Tamoxifen-resistant cells and down-regulated ERα-dependent genes. Most importantly, VPC-16606 successfully inhibited known constitutively active mutant forms of ERα observed in clinical settings where BCa patients have relapsed on aromatase inhibitors. Furthermore, the compound also reduced tumor burden in vivo. Overall, these studies helped to identify a novel class of ERα AF2 inhibitors which have the potential to effectively inhibit ERα activity by a unique mechanism and to circumvent the issue of hormone resistance in BCa patients.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat