Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries

Wang, Bo; Liu, Jin; Tandon, Ira; Wu, Suzhen; Teng, P. K.; Liao, Jianhua; Tang, Weiping

doi:10.1016/j.ejmech.2021.113425

Cited by 41 publications

(33 citation statements)

References 44 publications

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“…In 2021, Tang group reported a series of MDM2 ligands which were designed and synthesized based on the four-component Ugi reaction, and then synthesized MDM2 degraders based on these ligands. 164 After extensive optimization based on antiproliferative activity and MDM2-degradation activity, the degrader 98 ( WB214 , Fig. 23 ) was determined to be the degrader with the best MDM2-degradation activity in leukemia cells.…”

Section: Protacs Targeting Cancer-related Targetsmentioning

confidence: 99%

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Cao

et al. 2022

Sig Transduct Target Ther

112

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PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article “PROTACs: great opportunities for academia and industry” in the journal, summarizing the representative compounds of PROTACs reported before the end of 2019. In the past 2 years, the entire field of protein degradation has experienced rapid development, including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage. In addition to PROTAC and molecular glue technology, other new degradation technologies are also developing rapidly. In this article, we mainly summarize and review the representative PROTACs of related targets published in 2020–2021 to present to researchers the exciting developments in the field of protein degradation. The problems that need to be solved in this field will also be briefly introduced.

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Section: Protacs Targeting Cancer-related Targetsmentioning

confidence: 99%

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Cao

et al. 2022

Sig Transduct Target Ther

112

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“…34 However, synthetic difficulty presents another hurdle limiting broad SAR investigations. Highly efficient synthetic reactions, such as click chemistry, 35 Staudinger ligation, 36 Buchwald-Hartwig amination, 37 the Ugi reaction, 38 and solid-phase synthesis, 39 have been successfully 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.…”

Section: General Strategies For the Design And Optimization Of Protacsmentioning

confidence: 99%

“…However, synthetic difficulty presents another hurdle limiting broad SAR investigations. Highly efficient synthetic reactions, such as click chemistry, 35 Staudinger ligation, 36 Buchwald‐Hartwig amination, 37 the Ugi reaction, 38 and solid‐phase synthesis, 39 have been successfully used in facial synthesis and rapidly expanding SAR studies of PROTACs. The following sections introduce general strategies and recent progress in PROTAC design.…”

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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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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“…The first type of PROTACs, based on nutlin or idasanutlin (RG7388), was developed with the representative CRBNbased MDM2 degraders shown in Figure 4. However, the number of these MDM2 degraders remains limited, owing to their challenging physicochemical profiles and limited degradation activity (e.g., WB214 and TW-32) [88]. Recently, the Wang group has reported a series of potent PROTAC MDM2 degraders, including MD-224 as a lead compound targeting the MDM2 protein to CRBN for degradation (Figure 4) [33].…”

Section: Protac Degraders Targeting Mdm2mentioning

confidence: 99%

PROTAC degraders with ligands recruiting MDM2 E3 ubiquitin ligase: an updated perspective

Han

Wei

Sun

2022

Acta Materia Medica

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Mouse double minute 2 (MDM2) is an oncogenic E3 ligase that effectively degrades the tumor suppressor p53. In the past two decades, many MDM2 inhibitors that disrupt MDM2-p53 binding have been discovered and developed. Given that MDM2 and p53 form an auto-regulatory loop, in which p53 undergoes targeted degradation as a substrate of MDM2, and p53 targets MDM2 for transcriptional upregulation, these MDM2 inhibitors have limited efficacy. After rapid in vivo clearance of the MDM2 inhibitors, p53 is degraded by accumulated MDM2. Fortunately, proteolysis targeting chimeras (PROTACs), a novel therapeutic strategy, overcome the limitations of MDM2 inhibitors. Several MDM2 inhibitors developed in the past two decades have been used in PROTAC technology in two applications: 1) binding and targeting endogenous MDM2 for PROTAC-based degradation and 2) binding endogenous MDM2 as a PROTAC E3 ligand for PROTAC-based degradation of other oncogenic proteins. In this review, we summarize current progress in the discovery and development of MDM2-based PROTAC drugs, and discuss future perspectives and challenges in their application as effective treatments for human cancer.

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Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries

Cited by 41 publications

References 44 publications

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Strategies for designing proteolysis targeting chimaeras (PROTACs)

PROTAC degraders with ligands recruiting MDM2 E3 ubiquitin ligase: an updated perspective

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