Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC

Yang, Fang; Wen, Yalei; Wang, Chaofan; Zhou, Yuee; Zhou, Yang; Zhang, Zhimin; Liu, Tongzheng; Lu, Xiaoyun

doi:10.1016/j.ejmech.2021.114088

Cited by 51 publications

(40 citation statements)

References 38 publications

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“…Therefore, the acrylamide structure of MRTX849 should be retained when developing irreversible or reversible covalent KRAS G12C PROTACs. 83,109,110…”

Section: Choice Of Poi Ligands Attachment Sitementioning

confidence: 99%

Chemistries of bifunctional PROTAC degraders

et al. 2022

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“…Therefore, the acrylamide structure of MRTX849 should be retained when developing irreversible or reversible covalent KRAS G12C PROTACs. 83,109,110…”

Section: Choice Of Poi Ligands Attachment Sitementioning

confidence: 99%

Chemistries of bifunctional PROTAC degraders

et al. 2022

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“…These PROTACs would be the solution for proteins for which only weak reversible ligands exist. Furthermore, it is relevant to mention that these covalently bound PROTACs are currently in preclinical development [ 19 – 21 ].…”

Section: Discussionmentioning

confidence: 99%

Clinical considerations for the design of PROTACs in cancer

et al. 2022

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Degradation of targeted proteins using proteolysis targeting chimeras (PROTACs) has gained momentum. A PROTAC is a bifunctional molecule that consists of three parts: a ligand that interacts with the protein to be degraded, another ligand that binds to an E3 ubiquitin ligase and a linker that connects both. Identification of the right proteins as targets to be degraded and a ligase that is highly expressed in tumors compare with normal tissue is mandatory, as can augment efficacy reducing toxicity. In this article we review the current development stage of PROTACs in cancer to categorize the best PROTAC construction. Targets including BCL2, CDK4 and MCL1 were highly expressed in all tumors; MCL1 was significantly increased in breast cancer and lung adenocarcinoma and CDK4 in colon adenocarcinoma. Degradation of CDK9, AURKA or PLK1, followed by BCL2, MCL1, PTPN11, BRD4, PTK2, showed a high dependency. Most ligases evaluated were not highly present in tumors except for MDM2 in breast, lung, prostate and gastric cancer. In non-transformed tissue MDM2 was the most abundant ligase, followed by cIAP and CRBN, and those with low expression included XIAP and VHL. MDM2 ligase coupled with inhibitors of the targets BCL2, BRD4, CDK9, PLK1 and MCL1 in stomach tumor, and MDM2 with PIK3C3 inhibitors in breast cancer, seems to be the best therapeutic strategy. Our results suggest potential options for the design of PROTACS in specific medical indications.

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“…Also, based on the structure of LC-2 , Lu group replaced its vinyl moiety to obtain a series of KRAS G12C degraders. 95 They found that degrader 49 ( YF135 , Fig. 12 ) had the best degradation activity in H358 and H23 cells.…”

Section: Protacs Targeting Cancer-related Targetsmentioning

confidence: 97%

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

Cao

et al. 2022

Sig Transduct Target Ther

110

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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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Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC

Cited by 51 publications

References 38 publications

Chemistries of bifunctional PROTAC degraders

Chemistries of bifunctional PROTAC degraders

Clinical considerations for the design of PROTACs in cancer

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

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