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Review
. 2021 Mar 30;6(14):9334-9343.
doi: 10.1021/acsomega.0c06362. eCollection 2021 Apr 13.

From Pure Antagonists to Pure Degraders of the Estrogen Receptor: Evolving Strategies for the Same Target

Madhusoodanan Mottamal  1 , Borui Kang  1 , Xianyou Peng  1 , Guangdi Wang  1
Affiliations
Review

From Pure Antagonists to Pure Degraders of the Estrogen Receptor: Evolving Strategies for the Same Target

Madhusoodanan Mottamal et al. ACS Omega. .

Abstract

Pure antiestrogens, or selective estrogen receptor degraders (SERDs), have proven to be effective in treating breast cancer that has progressed on tamoxifen and/or aromatase inhibitors. However, the only FDA-approved pure antiestrogen, fulvestrant, is limited in efficacy by its low bioavailability. The search for orally bioavailable SERDs has continued for nearly as long as the clinical history of the injection-only fulvestrant. Oral SERDs that have been developed and tested in patients ranged from nonsteroidal ER binders containing an acrylic acid or amino side chain to bifunctional proteolysis-targeting chimera (PROTAC) pure ER degraders. Structural evolution in the development of oral SERD molecules has been closely associated with quantifiable ER-degrading potency, as seen in the structural comparison analysis of acrylic acid and basic amino side-chain-bearing SERDs. Failure to improve on fulvestrant in the clinical trials by numerous acidic SERDs and early basic SERDs is blamed on tolerability and/or insufficient efficacy, which will likely be overcome by the new-generation basic SERD molecules and PROTAC ER degraders with improved oral bioavailability, low toxicity, and superior efficacy of receptor degradation.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of pure antiestrogens.
Figure 2
Figure 2
Structures of orally available SERDs with an acrylic acid functional group.
Figure 3
Figure 3
Structures of oral SERDs with a basic side chain.
Figure 4
Figure 4
Comparison of the crystal structures of ERα in active (agonist-bound) and inactive (antagonist-bound) conformations. (A) Active form when bound to Estradiol (E2) and a short peptide from TIF2 transcriptional coactivator bearing canonical LXXLL motif (PDB code: 1GWR) and (B) inactive form when bound to bazedoxifene (BZA) (PDB code: 4XI3). In the antagonist-bound conformation, H12 is repositioned to occupy the coactivator binding groove.
Figure 5
Figure 5
Overlay of the X-ray crystal structure of ERα in complex with AZD9496 (green compound and purple ribbon) (5ACC) and docked model of ERα in complex with AZD9833 (blue compound and purple ribbon). Amino acids that make hydrogen bonds with the protein and key hydrophobic residues on H12 and H3 that are in the hydrophobic interface are shown in the stick model. Distances between the side chain δC of Leu539 and the side chains of AZD compounds are 3.5 and 6.7 Å, for the fluorine atom of AZD9833 and the carboxyl of AZD9496, respectively.
Figure 6
Figure 6
(A) Backbone root-mean-square deviations of the protein in the 100 ns MD simulations for ERα-AZD9833 (maroon) and ERα-AZD9496 (blue). (B) Root-mean-square fluctuations of ERα LBD residues in the 100 ns MD simulations for ERα-AZD9833 (maroon) and ERα-AZD9496 (blue).
Figure 7
Figure 7
PROTAC ER degraders.
See this image and copyright information in PMC

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