Estrogen Receptor-α Targeting: PROTACs, SNIPERs, Peptide-PROTACs, Antibody Conjugated PROTACs and SNIPERs

Abstract

Targeting selective estrogen subtype receptors through typical medicinal chemistry approaches is based on occupancy-driven pharmacology. In occupancy-driven pharmacology, molecules are developed in order to inhibit the protein of interest (POI), and their popularity is based on their virtue of faster kinetics. However, such approaches have intrinsic flaws, such as pico-to-nanomolar range binding affinity and continuous dosage after a time interval for sustained inhibition of POI. These shortcomings were addressed by event-driven pharmacology-based approaches, which degrade the POI rather than inhibit it. One such example is PROTACs (Proteolysis targeting chimeras), which has become one of the highly successful strategies of event-driven pharmacology (pharmacology that does the degradation of POI and diminishes its functions). The selective targeting of estrogen receptor subtypes is always challenging for chemical biologists and medicinal chemists. Specifically, estrogen receptor α (ER-α) is expressed in nearly 70% of breast cancer and commonly overexpressed in ovarian, prostate, colon, and endometrial cancer. Therefore, conventional hormonal therapies are most prescribed to patients with ER + cancers. However, on prolonged use, resistance commonly developed against these therapies, which led to selective estrogen receptor degrader (SERD) becoming the first-line drug for metastatic ER + breast cancer. The SERD success shows that removing cellular ER-α is a promising approach to overcoming endocrine resistance. Depending on the mechanism of degradation of ER-α, various types of strategies of developed.

Site-Specific Antibody Conjugation with Payloads beyond Cytotoxins

“…The PROTAC technology makes it feasible for effective degradation of many intracellular protein targets, such as tyrosine kinases, hormone receptors, and transcription factors which are often undruggable via many conventional inhibitors. It also provides different mechanism of actions (event-driven pharmacology) as compared to conventional inhibitors (occupancy-driven pharmacology) [ 75 ]. Its potential to expand the application in drug discovery has generated great interests, resulting in significant progress during the last decade with several PROTAC degraders reaching clinical trials [ 75 , 76 ].…”

“…It also provides different mechanism of actions (event-driven pharmacology) as compared to conventional inhibitors (occupancy-driven pharmacology) [ 75 ]. Its potential to expand the application in drug discovery has generated great interests, resulting in significant progress during the last decade with several PROTAC degraders reaching clinical trials [ 75 , 76 ]. However, there are still some challenges associated with physico-chemical properties of some degraders such as relatively large entities that may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetics [ 53 ].…”

“…The conjugate was internalized, resulting in active PROTAC for BRD4 degradation only in HER2 positive breast cancer cell lines in vitro. Furthermore, the field on selective degradation of estrogen receptor has also been advanced [ 75 ]. The site-specific antibody conjugation was described by using degraders that target estrogen receptor alpha (ERα) [ 50 , 77 ].…”

PROTACs: A novel strategy for cancer drug discovery and development

“…MDM2 is an E3 ubiquitin ligase that promotes tumor development by binding to the tumor suppressor p53 for degradation 335–342 . Over the past 20 years, a number of MDM2 inhibitors were used in the discovery of PROTAC degraders, like RG7388 and Nutlin‐3 series (Figure 4).…”

Indene-Derived Hydrazides Targeting Acetylcholinesterase Enzyme in Alzheimer’s: Design, Synthesis, and Biological Evaluation

“…Interestingly, donepezil is an indene-1-one analog, which shows preferential selectivity towards AChE than BChE. However, indene scaffolds are also devised to develop Mcl-1 inhibitors [ 11 ], estrogen-targeting compounds [ 12 , 13 ], and naturally derived fungal metabolites [ 12 ], as shown in Figure 1 B.…”