Target protein degradation by protacs: A budding cancer treatment strategy

Choudhary, Diksha; Kaur, Amritpal; Singh, Pargat; Chaudhary, Gaurav; Kaur, Rajwinder; Bayan, Mohammad F.; Chandrasekaran, Balakumar; Marji, Saeed M.; Ayman, Reema

doi:10.1016/j.pharmthera.2023.108525

Cited by 8 publications

(4 citation statements)

References 152 publications

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“…Besides, PD-1 and PD-L1, whether other immune checkpoint factors are regulated by PTMs and involve in cancer immunotherapy. Although PROTACs have many advantages, such as modularity, targeting on undruggable targets, selectivity, specificity and compatibility, they have several disadvantages, including heavy-molecular weight, unclear pharmacokinetics ( 67 ). It is necessary to develop more general strategies for PROTAC-mediated protein degradation.…”

Section: Discussionmentioning

confidence: 99%

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PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

Ren,

Wang,

Liu

et al. 2024

Front. Immunol.

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Immunotherapy has been developed, which harnesses and enhances the innate powers of the immune system to fight disease, particularly cancer. PD-1 (programmed death-1) and PD-L1 (programmed death ligand-1) are key components in the regulation of the immune system, particularly in the context of cancer immunotherapy. PD-1 and PD-L1 are regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation and glycosylation. PROTACs (Proteolysis Targeting Chimeras) are a type of new drug design technology. They are specifically engineered molecules that target specific proteins within a cell for degradation. PROTACs have been designed and demonstrated their inhibitory activity against the PD-1/PD-L1 pathway, and showed their ability to degrade PD-1/PD-L1 proteins. In this review, we describe how PROTACs target PD-1 and PD-L1 proteins to improve the efficacy of immunotherapy. PROTACs could be a novel strategy to combine with radiotherapy, chemotherapy and immunotherapy for cancer patients.

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Section: Discussionmentioning

confidence: 99%

“…AbTAC, molecular glue, LYTAC and Nano-PROTAC have been emerged to target proteins ( 66 ). PROTACs have been gaining attention in the field of drug development, particularly for their potential in treating diseases such as cancer, where certain proteins are overexpressed or mutated ( 67 , 68 ).…”

Section: Protacsmentioning

confidence: 99%

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

Ren,

Wang,

Liu

et al. 2024

Front. Immunol.

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“…Additional novel DYRK1A inhibitors have been identified that can induce DYRK1A degradation that can be useful for decreasing the dosage of the expressed protein in AD and DS , but further research is required to evaluate their potential for therapeutic use ( Branca et al, 2017 ; Melchior et al, 2019 ; Velazquez et al, 2019 ). Finally, normalization of the DYRK1A function in AD and DS could be achieved by developing the approaches for decreasing the protein levels without targeting its catalytic activity, such as use of PROteolysis Targeting Chimeras (PROTACs) ( Choudhary et al, 2023 ; Thomas et al, 2023 ).…”

Section: Dyrk1a In Human Disease and Therapeutic Developmentmentioning

confidence: 99%

Insights from the protein interaction Universe of the multifunctional “Goldilocks” kinase DYRK1A

Ananthapadmanabhan,

Shows,

Dickinson

et al. 2023

Front. Cell Dev. Biol.

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Human Dual specificity tyrosine (Y)-Regulated Kinase 1A (DYRK1A) is encoded by a dosage-dependent gene located in the Down syndrome critical region of human chromosome 21. The known substrates of DYRK1A include proteins involved in transcription, cell cycle control, DNA repair and other processes. However, the function and regulation of this kinase is not fully understood, and the current knowledge does not fully explain the dosage-dependent function of this kinase. Several recent proteomic studies identified DYRK1A interacting proteins in several human cell lines. Interestingly, several of known protein substrates of DYRK1A were undetectable in these studies, likely due to a transient nature of the kinase-substrate interaction. It is possible that the stronger-binding DYRK1A interacting proteins, many of which are poorly characterized, are involved in regulatory functions by recruiting DYRK1A to the specific subcellular compartments or distinct signaling pathways. Better understanding of these DYRK1A-interacting proteins could help to decode the cellular processes regulated by this important protein kinase during embryonic development and in the adult organism. Here, we review the current knowledge of the biochemical and functional characterization of the DYRK1A protein-protein interaction network and discuss its involvement in human disease.

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“…PROTACs have been shown to be able to overcome some of the disadvantages of conventional therapies, with very promising results, both in vitro and in vivo. 36 , 37 , 38 In such a way that they have progressed through various stages of preclinical and clinical development for the treatment of several types of diseases, with a special focus on cancer treatment. 39 , 40 Consequently, the study of its therapeutic potential in a wide range of diseases, including leukemia, has been very extensive.…”

Section: Introductionmentioning

confidence: 99%

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

Vicente,

Salvador

2024

MedComm

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Leukemia is a heterogeneous group of life‐threatening malignant disorders of the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among the approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, and long‐term sequelae occur in a significant proportion of patients and severely compromise the treatment efficacy. The development of novel approaches to improve outcomes is therefore an unmet need. Recently, novel leukemia drug discovery strategies, including targeted protein degradation, have shown potential to advance the field of personalized medicine for leukemia patients. Specifically, PROteolysis‐TArgeting Chimeras (PROTACs) are revolutionary compounds that allow the selective degradation of a protein by the ubiquitin–proteasome system. Developed against a wide range of cancer targets, they show promising potential in overcoming many of the drawbacks associated with conventional therapies. Following the exponential growth of antileukemic PROTACs, this article reviews PROTAC‐mediated degradation of leukemia‐associated targets. Chemical structures, in vitro and in vivo activities, pharmacokinetics, pharmacodynamics, and clinical trials of PROTACs are critically discussed. Furthermore, advantages, challenges, and future perspectives of PROTACs in leukemia are covered, in order to understand the potential that these novel compounds may have as future drugs for leukemia treatment.

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Target protein degradation by protacs: A budding cancer treatment strategy

Cited by 8 publications

References 152 publications

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

Insights from the protein interaction Universe of the multifunctional “Goldilocks” kinase DYRK1A

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

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