PROTAC: targeted drug strategy. Principles and limitations

Koroleva, O. A.; Dutikova, Yu. V.; Trubnikov, A.V.; Zenov, F. A.; Manasova, E. V.; Shtil, Alexander А.; Kurkin, A. V.

doi:10.1007/s11172-022-3659-z

Cited by 14 publications

(9 citation statements)

References 181 publications

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Section: Discussionmentioning

confidence: 99%

“…This reveals a new perspective for developing molecular markers for tumor response to treatment. For such situations, the combination of single-target drugs or the development of "dual-action" compounds using PROTAC technology [56] for simultaneous inactivation of ATOX1 and Attention should be paid to the contribution of reactive oxygen species (ROS) to Atox1 and cyclin D1 activity, as Atox1 is involved in regulating the redox balance by stimulating ROS production through NADPH oxidase activation. This contradicts the initial hypothesis about copper chaperones as an ROS elimination factors, but explains its p53-dependent suppression [32,57,58].…”

Section: Bleomycin-induced P53 Activation Leads To the Suppression Ofmentioning

confidence: 99%

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Atox1-Cyclin D1 Loop Activity is Critical for Survival of Tumor Cells with Inactivated TP53

Kuchur,

Pogodaeva,

Shcherbakova

et al. 2024

Preprint

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The search for relevant molecular targets is one of the main tasks of modern tumor chemotherapy. To successfully achieve this, it is necessary to have the most complete understanding of the functioning of the cell's transcriptional apparatus, particularly related to proliferation. The p53 protein plays an important role in regulating processes such as apoptosis, repair, and cell division, and the loss of its functionality often accompanies various types of tumors and contributes to the development of chemoresistance. Additionally, the proliferative activity of tumor cells is closely related to the metabolism of transition metals. For example, the metallochaperone Atox1, a copper transporter protein, acts as a transcription activator for cyclin D1, promoting progression through the G1/S phase of the cell cycle. On the other hand, p53 suppresses cyclin D1 at the transcriptional level, thereby these proteins have divergent effects on cell cycle progression. However, the contribution of the interaction between these proteins to cell survival is poorly understood. This work demonstrates that there not only exists a positive feedback loop between Atox1 and cyclin D1, but also that the activity of this loop depends on the status of the TP53 gene. Upon inactivation of TP53 in A549 and HepG2 cell lines, the expression of ATOX1 and CCND1 genes is enhanced, and their suppression in these cells leads to pronounced apoptosis. This fundamental observation may be useful in selecting more precise interventions for combined therapy of p53-negative tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Bleomycin-induced P53 Activation Leads To the Suppression Ofmentioning

confidence: 99%

Atox1-Cyclin D1 Loop Activity is Critical for Survival of Tumor Cells with Inactivated TP53

Kuchur,

Pogodaeva,

Shcherbakova

et al. 2024

Preprint

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“…Therefore, even if the affinity between the POI and PROTAC is reduced due to mutations, as long as recruitment of the E3 ligase remains intact, degradation can still occur. This unique mode of action makes it more difficult for cancer cells to develop resistance mechanisms, as they cannot simply bypass the inhibition and continue functioning. − It highlights the potential of PROTACs to provide new opportunities for improved selectivity profile, reduced off-target effects, overcoming drug resistance, and expanding therapeutic options in drug development (Figure ). , …”

Section: Introductionmentioning

confidence: 99%

Recent Progress in DNA Damage Response-Targeting PROTAC Degraders

Cheng,

Fei,

Ding

et al. 2024

J. Med. Chem.

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DNA damage response (DDR) defects in cells play a crucial role in tumor development by promoting DNA mutations. These mutations create vulnerabilities specific to cancer cells, which can be effectively targeted through synthetic lethality-based therapies. To date, numerous small molecule DDR inhibitors have been identified, and some of them have already been approved for clinical use. However, due to the complexity of the tumor microenvironment, mutations may occur in the amino acid residues of DDR targets. These mutations can affect the efficacy of small molecule inhibitors targeting DDR pathways. Therefore, researchers have turned their attention to next-generation DNA damage repair modulators, particularly those based on PROTAC technology. From this perspective, we overviewed the recent progress on DDR-targeting PROTAC degraders for cancer therapy. In addition, we also summarized the biological functions of different DDR targets. Finally, the challenges and future directions for DDR-target PROTAC degraders are also discussed in detail. ■ SIGNIFICANCECurrently, PROTAC degraders have been widely applied in the field of DDR-targeted drug discovery. This Perspective aims to provide a comprehensive overview of the current status and future perspectives in DDR-targeting PROTAC degraders for cancer therapy. Furthermore, it offers valuable insights into the rational design strategies and hurdles encountered during the development of DDR-targeting PROTAC degraders.

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“…A typical PROTAC degrader consists of three components: the target‐binding small molecule ligand (protein of interest, POI), the E3 ligase ligand and the appropriate linker that connects the two components (Figure 1). 50,66–73 E3 ligases and the corresponding ligands are important as the driving force of protein degradation 74–91 . Good drug‐like small‐molecule ligands for a E3 ligase system are still limited 92–97 .…”

Section: Introductionmentioning

confidence: 99%

“… 50 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 E3 ligases and the corresponding ligands are important as the driving force of protein degradation. 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 Good drug‐like small‐molecule ligands for a E3 ligase system are still limited. 92 , 93 , 94 , 95 , 96 , 97 Although more than 600 E3 ligases are encoded by human genome, only less than 10 E3 ligases were developed as ligands for the development of PROTAC degraders, including von Hippel‐Lindau (VHL), cereblon (CRBN), mouse double minute 2 (MDM2), cellular IAP1 (cIAP1), Kelch‐like ECH‐associated protein‐1 (KEAP1), DDB1‐cullin 4‐associated factor (DCAF), RING finger protein (RNF), aryl hydrocarbon receptor (AHR), and others (Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

PROTACs: A novel strategy for cancer drug discovery and development

Han

Sun

2023

MedComm

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Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: a small molecule that binds to a target protein, an E3 ligase ligand (consisting of an E3 ligase and its small molecule recruiter), and a chemical linker that hooks first two components together. In the past 20 years, we have witnessed advancement of multiple PRO-TAC degraders into the clinical trials for anticancer therapies. However, one of the major challenges of PROTAC technology is that only very limited number of E3 ligase recruiters are currently available as E3 ligand for targeted protein degradation (TPD), although human genome encodes more than 600 E3 ligases. Thus, there is an urgent need to identify additional effective E3 ligase recruiters for TPD applications. In this review, we summarized the existing RING-type E3 ubiquitin ligase and their small molecule recruiters that act as effective E3 ligands of PRO-TAC degraders and their application in anticancer drug discovery. We believe that this review could serve as a reference in future development of efficient E3 ligands of PROTAC technology for cancer drug discovery and development.

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PROTAC: targeted drug strategy. Principles and limitations

Cited by 14 publications

References 181 publications

Atox1-Cyclin D1 Loop Activity is Critical for Survival of Tumor Cells with Inactivated TP53

Atox1-Cyclin D1 Loop Activity is Critical for Survival of Tumor Cells with Inactivated TP53

Recent Progress in DNA Damage Response-Targeting PROTAC Degraders

PROTACs: A novel strategy for cancer drug discovery and development

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