Abstract
Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor α positive (ERα+) making it a critical therapeutic target. With that, the two subtypes of ER, ERα and ERβ, have contrasting effects on BCa cells. While ERα promotes cancerous activities, ERβ isoform exhibits inhibitory effects on the same. ER-directed small molecule drug discovery for BCa has provided the FDA approved drugs tamoxifen, toremifene, raloxifene and fulvestrant that all bind to the estrogen binding site of the receptor. These ER-directed inhibitors are non-selective in nature and may eventually induce resistance in BCa cells as well as increase the risk of endometrial cancer development. Thus, there is an urgent need to develop novel drugs with alternative ERα targeting mechanisms that can overcome the limitations of conventional anti-ERα therapies. Several functional sites on ERα, such as Activation Function-2 (AF2), DNA binding domain (DBD), and F-domain, have been recently considered as potential targets in the context of drug research and discovery. In this review, we summarize methods of computer-aided drug design (CADD) that have been employed to analyze and explore potential targetable sites on ERα, discuss recent advancement of ERα inhibitor development, and highlight the potential opportunities and challenges of future ERα-directed drug discovery.
Highlights
Elacestrant/RAD1901 is a SERM/SERD hybrid substance developed by Hattersley et al for Radius Pharmaceuticals in 2015, and is currently in Phase III trial aiming to compare its safety and efficacy to the standard endocrine therapy in combination with fulvestrant or AI in advanced ERα+/HERsetting [262]
Elacestrant/RAD1901 is a SERM/SERD hybrid substance developed by Hattersley et al for Radius Pharmaceuticals in 2015, and is currently in Phase III trial aiming to compare its safety and efficacy to the standard endocrine therapy in combination with fulvestrant or AI in advanced ERα+/HER- setting [262]
Nude mice xenografted with MCF-7 cells and injected with 10 mg/kg TD-PROTAC resulted in 75% reduction in tumor volume in 42 days similar to 4 mg/kg tamoxifen in comparison with the control untreated tumor [277]
Summary
Breast cancer (BCa) is the most common lethal cancer in women with projected 279,100 new cases and 42,690 deaths in the United States alone this year [1,2]. Incidence rates have been increasing, the BCa mortality in North America and the European Union (EU) has decreased This is attributable mostly to early detection, efficient systemic therapies, and the continual focus on developing better drugs for treatment and prevention of BCa [3]. CCoommppuutteerr AAiiddeedd DDrruugg DDeessiiggnn ffoorr EEssttrrooggeenn RReecceeppttoorr IInnhhiibbiittoorrss EEmmppiirriiccaall tteecchhnniiqquueess hhaavvee bbeeeenn ccoonnvveennttiioonnaallllyy uusseedd iinn EERR ddrruugg ddeevveellooppmmeenntt;; aanndd llaatteerr eexxppeerriimmeennttaall--bbaasseedd hhiigghh tthhrroouugghhppuutt ssccrreeeenniinngg ((HHTTSS)) ppllaayyeedd aann iimmppoorrttaanntt rroollee ffoorr tthhee iiddeennttiifificcaattiioonn ooff ppootteennttiiaall hhiittss. An alternative strategy to develop inhibitors for proteins with no solved structure is to use ligand based drug design (LBDD) approaches. This strategy requires pre-existing activity data of known ligands. We present the recent advancements in ERα inhibitor development and highlight the potential opportunities and challenges of future ERα-directed small molecule inhibitor development
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