Exploring the PROTAC degron candidates: OBHSA with different side chains as novel selective estrogen receptor degraders (SERDs)

Li, Yuanyuan; Zhang, Silong; Zhang, Jing; Hu, Zhigang; Yuan, Xiao; Huang, Jian; Dong, Chune; Huang, Shengtang; Zhou, Hai‐Bing

doi:10.1016/j.ejmech.2019.03.058

Cited by 34 publications

(18 citation statements)

References 45 publications

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“…For proteins without known ligands, structural modification of a substrate may lead to the generation of a compound capable of competing with the substrate for the binding pocket and thus can be used as ligands for PROTAC design. For proteins with numerous inhibitors, the binding affinity, physicochemical properties and synthetic feasibility are important factors in ligand selection 40–42 . Compared with that of small‐molecule inhibitors, the efficacy of PROTACs has a low correlation with the binding affinity of ligands for a POI because even temporary binding is enough to induce degradation.…”

Section: General Strategies For the Design And Optimization Of Protacsmentioning

confidence: 99%

“…For proteins with numerous inhibitors, the binding affinity, physicochemical properties and synthetic feasibility are important factors in ligand selection. [40][41][42] Compared with that of small-molecule inhibitors, the efficacy of PROTACs has a low correlation with the binding affinity of ligands for a POI because even temporary binding is enough to induce degradation. Theoretically, all POI ligands could be applied to the design of a PROTAC.…”

Section: General Strategies For the Design And Optimization Of Protacsmentioning

confidence: 99%

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Strategies for designing proteolysis targeting chimaeras (PROTACs)

Dong

Cheng

et al. 2022

Medicinal Research Reviews

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Proteolysis targeting chimaeras (PROTACs) is a cutting edge and rapidly growing technique for new drug discovery and development. Currently, the largest challenge in the molecular design and drug development of PROTACs is efficient identification of potent and drug-like degraders. This review aims to comprehensively summarize and analyse state-ofthe-art methods and strategies in the design of PROTACs.We provide a detailed illustration of the general principles and tactics for designing potent PROTACs, highlight representative case studies, and discuss the advantages and limitations of these strategies. Particularly, structure-based rational PROTAC design and emerging new types of PROTACs (e.g., homo-PROTACs, multitargeting PROTACs, photo-control PROTACs and PROTAC-based conjugates) will be focused on.

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Section: General Strategies For the Design And Optimization Of Protacsmentioning

confidence: 99%

Section: General Strategies For the Design And Optimization Of Protacsmentioning

confidence: 99%

Strategies for designing proteolysis targeting chimaeras (PROTACs)

Dong

Cheng

et al. 2022

Medicinal Research Reviews

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“…PROTAC-2, PROTAC-B, compound 24, compound 11, and estrogen receptor degrader (ERD)-148, among other PROTACs, have been designed to induce the reduction of ERα levels in BC cells (Figure 3) [99][100][101]. PROTAC-2 was designed with an estradiol molecule to bind to ERα and the phosphopeptide of IκBα that recruits SCF β-trcp Ub ligase complex, leading to ERα degradation [102].…”

Section: Protacs For Erαmentioning

confidence: 99%

Proteolysis-targeting chimeras and their implications in breast cancer

Tecalco-Cruz

Zepeda–Cervantes

Ramírez-Jarquín

et al. 2021

Exploration of Targeted Anti-Tumor Therapy

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Breast cancer (BC) is a highly heterogeneous neoplasm of the mammary tissue, causing the deaths of a large number of women worldwide. Nearly 70% and 20% of BC cases are estrogen receptor alpha positive (ERα+) and human epidermal growth factor receptor 2-positive (HER2+), respectively; therefore, ER and HER2 targeted therapies have been employed in BC treatment. However, resistance to these therapies has been reported, indicating a need for developing novel therapeutic strategies. Proteolysis-targeting chimeras (PROTACs) are new, promising therapeutic tools designed with a bimodular structure: one module allows specific binding to target proteins, and the other module allows efficient degradation of these target proteins. In this paper, PROTACs and their potential in controlling the progression of ERα and HER2+ BC are discussed.

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“…In general, compounds with basic side chains (Table16, 153-155) were efficient ERα degraders and moderate antiproliferative agents (IC 50 values in the micromolar range). [87] Docking studies revealed the formation of a novel hydrogen bond between the basic side chain and Thr-347 in addition to hydrophobic repulsion with the backbone of Met343, which would drive h3 distortion. However, some of the analogues with basic side chains did not exhibit potency to degrade ERα.…”

Section: Oxabicycloheptene Sulfonamides (Obhsa)mentioning

confidence: 99%

The Quest for Orally Available Selective Estrogen Receptor Degraders (SERDs)

Wang

Sharma

2020

ChemMedChem

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Research Institute in 1994, have been reported as promising orally bioavailable SERDs. Some of these compounds are currently in clinical trials, while various other structurally novel SERDs have also been reported by pharma as well as academic research groups. This review provides a critical analysis of the recent developments in orally available SERDs, with a focus on the structure-activity relationships, binding interactions and pharmacokinetic properties of these compounds [a

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Exploring the PROTAC degron candidates: OBHSA with different side chains as novel selective estrogen receptor degraders (SERDs)

Cited by 34 publications

References 45 publications

Strategies for designing proteolysis targeting chimaeras (PROTACs)

Strategies for designing proteolysis targeting chimaeras (PROTACs)

Proteolysis-targeting chimeras and their implications in breast cancer

The Quest for Orally Available Selective Estrogen Receptor Degraders (SERDs)

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