Discovery of BP3 as an efficacious proteolysis targeting chimera (PROTAC) degrader of HSP90 for treating breast cancer

Liu, Quanyu; Tu, Guihui; Hu, Yan; Jiang, Qingna; Li, Jingwen; Lin, Shujing; Yu, Zelei; Li, Ge; Wu, Xinhua; Tang, Yuanling; Huang, Xiuwang; Xu, Jianhua; Liu, Yang; Wu, Lixian

doi:10.1016/j.ejmech.2021.114013

Cited by 23 publications

(8 citation statements)

References 35 publications

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“…Wu group designed and synthesized a series of PROTACs based on the binding mode of HSP90 inhibitor BIIB021 to the protein. 378 Then they tested their degradation activity on HSP90 protein and proliferation inhibitory activity in MCF-7 and MDA-MB-231 cells, they found the degrader 202 ( BP3 , Fig. 57 ) could induce the degradation of HSP90 protein with a DC 50 of 0.99 µM and an IC 50 of 0.63 µM for cell proliferation inhibitory activity in MCF-7 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

136

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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

136

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“…Cancer cells overexpress heat shock protein 90 (Hsp90), reflecting their need to maintain protein homeostasis during stress conditions [ 40 , 41 , 42 ]. Hsp90s are drug targets in cancer therapy, but most Hsp90 inhibitors failed in clinical trials due to liver, ocular and cardiac toxicities [ 43 , 44 ]. Chae and his colleagues tried to address the existing interplay between Hsp90 and HDAC, as HDAC is believed to be vital for the development of resistance towards Hsp90 inhibitors, suggesting that the dual inhibition of Hsp90 and HDAC might overcome the issues that single inhibition of Hsp90 pose ( Figure 4 ) [ 45 , 46 ].…”

Section: Hybrids Of Natural Products With Small Moleculesmentioning

confidence: 99%

Recent Advances in Natural Product-Based Hybrids as Anti-Cancer Agents

et al. 2022

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Cancer is one of the top leading causes of death worldwide. It is a heterogenous disease characterized by unregulated cell proliferation and invasiveness of abnormal cells. For the treatment of cancer, natural products have been widely used as a source of therapeutic ingredients since ancient times. Although natural compounds and their derivatives have demonstrated strong antitumor activity in many types of cancer, their poor pharmacokinetic properties, low cell selectivity, limited bioavailability and restricted efficacy against drug-resistant cancer cells hinder their wide clinical application. Conjugation of natural products with other bioactive molecules has given rise to a new field in drug discovery resulting to the development of novel, bifunctional and more potent drugs for cancer therapy to overcome the current drawbacks. This review discusses multiple categories of such bifunctional conjugates and highlights recent trends and advances in the development of natural product hybrids. Among them, ADCs, PDCs, ApDCs, PROTACs and AUTOTACs represent emerging therapeutic agents against cancer.

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“…There are several types of cancer in which the HSP90 protein is excessively activated, and as this is a protein responsible for regulating, stabilizing, and activating many other proteins, some of which are even considered oncogenic, like epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2), any deregulation in the signaling pathways of the cells can lead to cancer progression [ 72 ]. Therefore, to carry out the degradation of this protein based on the fact that its inhibition has a moderate anticancer effect, although with some toxic effects, several MDM2-based PROTACs (PROTACs H) were developed with different types of linkers, which recruit the target protein through the BIIB021 inhibitor and MDM2 through idasanutlin [ 72 ]. However, PROTACs that recruit E3 ligase CRBN are more effective in degrading HSP90 [ 72 ].…”

Section: Protacs That Recruit Mdm2 E3 Ligasementioning

confidence: 99%

“…Therefore, to carry out the degradation of this protein based on the fact that its inhibition has a moderate anticancer effect, although with some toxic effects, several MDM2-based PROTACs (PROTACs H) were developed with different types of linkers, which recruit the target protein through the BIIB021 inhibitor and MDM2 through idasanutlin [ 72 ]. However, PROTACs that recruit E3 ligase CRBN are more effective in degrading HSP90 [ 72 ].…”

Section: Protacs That Recruit Mdm2 E3 Ligasementioning

confidence: 99%

“… Chemical structure of some MDM2-based PROTACs intended for the treatment of breast cancer. The PROTACs E1 and E2 target the tropomyosin receptor kinase C (TrkC) [ 69 ]; the F1 and F2 PROTACs target the estrogen-related receptor α (ERRα) [ 70 ]; PROTACs G, with diverse types of linkers, degrade cyclin-dependent kinase 6 (CDK6) [ 71 ]; PROTACs H degrade heat shock protein 90 (HSP90) [ 72 ]. …”

Section: Protacs That Recruit Mdm2 E3 Ligasementioning

confidence: 99%

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MDM2-Based Proteolysis-Targeting Chimeras (PROTACs): An Innovative Drug Strategy for Cancer Treatment

Vicente

Salvador

2022

IJMS

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Proteolysis-targeting chimeras (PROTACs) are molecules that selectively degrade a protein of interest (POI). The incorporation of ligands that recruit mouse double minute 2 (MDM2) into PROTACs, forming the so-called MDM2-based PROTACs, has shown promise in cancer treatment due to its dual mechanism of action: a PROTAC that recruits MDM2 prevents its binding to p53, resulting not only in the degradation of POI but also in the increase of intracellular levels of the p53 suppressor, with the activation of a whole set of biological processes, such as cell cycle arrest or apoptosis. In addition, these PROTACs, in certain cases, allow for the degradation of the target, with nanomolar potency, in a rapid and sustained manner over time, with less susceptibility to the development of resistance and tolerance, without causing changes in protein expression, and with selectivity to the target, including the respective isoforms or mutations, and to the cell type, overcoming some limitations associated with the use of inhibitors for the same therapeutic target. Therefore, the aim of this review is to analyze and discuss the characteristics of MDM2-based PROTACs developed for the degradation of oncogenic proteins and to understand what potential they have as future anticancer drugs.

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Discovery of BP3 as an efficacious proteolysis targeting chimera (PROTAC) degrader of HSP90 for treating breast cancer

Cited by 23 publications

References 35 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)

Recent Advances in Natural Product-Based Hybrids as Anti-Cancer Agents

MDM2-Based Proteolysis-Targeting Chimeras (PROTACs): An Innovative Drug Strategy for Cancer Treatment

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