Haibing Zhou
Wuhan University School of Pharmaceutical Sciences
Estrogens are now recognized to be major regulators of physiological functions in both reproductive and nonreproductive tissues in both men and women,1 whose pro-proliferative effects in many target tissues can be pathological,2 such as breast cancer. Both estrogens and antiestrogens work through the estrogen receptors, of which there are two subtypes, ERα and ERβ. The distinct patterns of tissue distribution of these two receptors have heightened interest in searching for selective estrogen receptor modulators, known as SERMs. Although current SERMs have clear advantages in the treatment of hormone-responsive breast cancer, they retain some disadvantages, for instance, tamoxifen therapy is ineffective for ER negative (ER(-)), and roughly half of ER positive (ER(+)) tumors are insensitive or lose response to continued tamoxifen therapy and gain resistance.3 Thus, much effort has been made to develop an “ideal SERM”, which is more effective or does not develop resistance. One strategy to develop such SERMs involves combining two bioactive motifs or drugs into a single molecule as a conjugate, which might be conferred desired therapeutical activity.4
In this presentation, we will report series of novel small molecules with dual regulation activity,5 which including novel hybrid compounds combining an indirect antagonism structure motif of ER (OBHS, oxabicycloheptene sulfonate)6 with suberoylanilide hydroxamic acid (SAHA) as dual-acting ER and histone deacetylase inhibitors;7 organometallic SERMs with anti-proliferative activity for both ER(+) and ER(-) resistance breast cancer cell; selective estrogen receptor downregulators (SERDs) for Tamoxifen resistance cancer cell etc. The dual regulation mechanism of these ligands will be investigated based on structural biology and computer-aided drug design. The feasibility of these new ligands as potential bifunctional drugs for breast cancer therapy has been investigated, and their structure-activity relationship (SAR), as well as the dual mechanism of the interaction of these ligands with ER will also be discussed.
References
(1) Gustafsson, J. A. Trends Pharmacol. Sci. 2003, 24, 479.
(2) Carruba, G. Ann. N. Y. Acad. Sci. 2006, 1089, 201.
(3) Clarke, R.; Liu, M. C.; Hilakivi-Clarke, L. A. et al. Oncogene. 2003, 22, 7316.
(4) Dao, K. L.; Hanson, R. N. Bioconjug. Chem. 2012, 23, 2139.
(5) Liao, Z.; Dong, C.; Katzenellenbogen, J. A.; Zhou, H.-B. et al. J. Med. Chem. 2014, 57, 3532.
(6) Zheng, Y. F.; Zhu, M. H.; Zhou, H. B. et al. ChemMedChem 2012, 7, 1094.
(7) Tang, C.; Li, C. H.; Zhang, S. L.; Zhou, H. B. et al. J. Med. Chem. 2015, 58, 4550.
