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

Arvind Negi, Kavindra Kumar Kesari, Anne Sophie Voisin-Chiret

Research output: Contribution to journalReview Articlepeer-review

9 Citations (Scopus)
86 Downloads (Pure)

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.

Original languageEnglish
Article number2523
Pages (from-to)1-43
Number of pages43
JournalPHARMACEUTICS
Volume14
Issue number11
DOIs
Publication statusPublished - Nov 2022
MoE publication typeA2 Review article, Literature review, Systematic review

Keywords

  • peptide PROTACs
  • SNIPERs
  • PORTACs
  • antibody-based PROTAC conjugate
  • clinical PROTACs
  • GROWTH-FACTOR-I
  • NF-KAPPA-B
  • PROSTATE-CANCER PROGRESSION
  • PROTEIN-PROTEIN INTERACTION
  • ACTIVATING ESR1 MUTATIONS
  • BETA-AGONISTS SERBAS
  • ER-ALPHA
  • SMALL MOLECULES
  • BINDING DOMAIN
  • BREAST-CANCER

Fingerprint

Dive into the research topics of 'Estrogen Receptor-α Targeting: PROTACs, SNIPERs, Peptide-PROTACs, Antibody Conjugated PROTACs and SNIPERs'. Together they form a unique fingerprint.

Cite this