Design, Synthesis, and Structure-Activity Relationships of Small Molecule ER-Beta Agonists for Glioblastoma
Introduction
Glioblastoma (GBM) is one of the most common and aggressive forms of primary malignant brain tumors in adults. Though the incidine of GBM is only 4.7 per 100,000, it puts chances of survival after 5 years at only 12%. At present, the treatments for GBM include radiation and chemotherapy; However, emerging resistance to these treatments is a problem. There is an unmet need of drugs to treat GBM, however, preliminary data suggests that agonists of estrogen receptor beta (ER-Beta) have tumor suppressive functions in GBM. Potent and selective agonists of ER-Beta are needed to address the lack of drugs to treat GBM.
Methods
To develop novel, potent, and selective ER-Beta agonists, the endogenous ligand estrogen is kept in mind. A phenol is maintained within the scaffold of the biaryl system to provide hydrogen bonding interactions within the enzyme pocket. The biaryl system also contains an indanone or tetralone opposite the phenol to provide selective for ER-Beta, which can be modulated to an oxime or keto-oxime to alter the pKa. All the requirements of these drugs are balanced with blood-brain barrier (BBB) and CNS penetrability and the achievability of their syntheses.
Results
Preliminary results have yielded two lead compounds, CIDD-0149897 and CIDD-0150184, both of the aryl indanone scaffold. These lead compounds are more potent and selective than the control compound, LY500307. The phenol and keto-oxime of the biaryl system were maintained, while small lipophilic groups on the aryl rings were introduced to enhance selectivity. The lead compounds are CNS penetrant and have moderate systemic exposure. The aforementioned tetralone scaffold is being expanded upon to fill in SAR gaps, which will direct future targets. ADME data is also being gathered.
Conclusion
Potent and selective ER-Beta agonists have been identified, which are active in vitro and in vivo. Compound CIDD-0149897 showed reduced tumor size in GBM mouse xenograft models. Current efforts are underway to address high plasma protein binding and improve aqueous solubility.