Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets

Wang, Yungang; Deng, Shouyan; Xu, Jin-Quan

doi:10.20892/j.issn.2095-3941.2020.0066

Cited by 8 publications

(8 citation statements)

References 144 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Following in the footsteps of immunotherapy, small-molecule-mediated activation of the immune response against tumours is a rich area of drug development 176 , 177 . PROTACs have the potential to be first-in-class medicines in immuno-oncology as small-molecule drugs that target immune cell activation to phenocopy PD1/PDL1-directed agents 178 , 179 . Most recently, PROTACs that target mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1; also known as HPK1) have been described with promising preclinical activity 180 , although HPK1 inhibitors were shown to be equally effective.…”

Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

1,271

996

View full text Add to dashboard Cite

Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin–proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development. With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’. In this Review, we summarize the first two decades of PROTAC discovery and assess the current landscape, with a focus on industry activity. We then discuss key areas for the future of TPD, including establishing the target classes for which TPD is most suitable, expanding the use of ubiquitin ligases to enable precision medicine and extending the modality beyond oncology.

show abstract

Section: Outlook For the Next 20 Years Of Tpdmentioning

confidence: 99%

PROTAC targeted protein degraders: the past is prologue

Békés

Langley

Crews

2022

Nat Rev Drug Discov

1,271

996

View full text Add to dashboard Cite

show abstract

“…In contrast, noncovalently tethered PROTAC molecules can be recovered and joined into the next circulation soon after protein degradation by the proteasome [ 19 , 25 ]. Collectively, as the next generation of small-molecule therapies, PROTAC-based drugs are expected to thoroughly replace macromolecular therapies in tumor immunotherapy [ 25 , 32 , 33 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

“…Despite the attractive prospect of applying PROTAC to immuno-oncology, few studies have focused on this issue, which might be attributed to the immature concepts and approaches. There are some existing reviews that refer to targeted protein degradation (TPD) strategies for tumor immunotherapy, but they merely focus on molecule designs and their applications in programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint [ 33 , 34 ]. The influence of PROTAC molecules in multiple events within the tumor microenvironment (TME), such as signal crosstalk, antigen presentation, immune cell invasion and tumor immunogenicity, are not mentioned in these review articles [ 4 , 33 , 34 , 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

“…There are some existing reviews that refer to targeted protein degradation (TPD) strategies for tumor immunotherapy, but they merely focus on molecule designs and their applications in programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint [ 33 , 34 ]. The influence of PROTAC molecules in multiple events within the tumor microenvironment (TME), such as signal crosstalk, antigen presentation, immune cell invasion and tumor immunogenicity, are not mentioned in these review articles [ 4 , 33 , 34 , 35 , 36 ]. Thus, it is required to summarize the current advances and discover more targets in PROTAC-mediated tumor immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Small-Molecule PROTACs for Cancer Immunotherapy

Liu¹,

Zhang²,

Xiang³

et al. 2022

Molecules

View full text Add to dashboard Cite

Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a Cancer Patients. Bosn. J. Basic novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.

show abstract

“…One of the most intriguing and novel therapeutic approaches involves the use of PROTAC (proteolysis-targeting chimeric molecules), which are hetero-bifunctional molecules that recruit specific target proteins to the E3 ligase, thus inducing the increase of target ubiquitination and degradation. This strategy has already been applied to the degradation of a number of selected targets [ 233 , 234 , 235 ]. However, even though promising, it is still in its infancy for application to immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

At the Cutting Edge against Cancer: A Perspective on Immunoproteasome and Immune Checkpoints Modulation as a Potential Therapeutic Intervention

Tundo

Sbardella

Oddone

et al. 2021

Cancers

View full text Add to dashboard Cite

Immunoproteasome is a noncanonical form of proteasome with enzymological properties optimized for the generation of antigenic peptides presented in complex with class I MHC molecules. This enzymatic property makes the modulation of its activity a promising area of research. Nevertheless, immunotherapy has emerged as a front-line treatment of advanced/metastatic tumors providing outstanding improvement of life expectancy, even though not all patients achieve a long-lasting clinical benefit. To enhance the efficacy of the currently available immunotherapies and enable the development of new strategies, a broader knowledge of the dynamics of antigen repertoire processing by cancer cells is needed. Therefore, a better understanding of the role of immunoproteasome in antigen processing and of the therapeutic implication of its modulation is mandatory. Studies on the potential crosstalk between proteasome modulators and immune checkpoint inhibitors could provide novel perspectives and an unexplored treatment option for a variety of cancers.

show abstract

Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets

Cited by 8 publications

References 144 publications

PROTAC targeted protein degraders: the past is prologue

PROTAC targeted protein degraders: the past is prologue

Small-Molecule PROTACs for Cancer Immunotherapy

At the Cutting Edge against Cancer: A Perspective on Immunoproteasome and Immune Checkpoints Modulation as a Potential Therapeutic Intervention

Contact Info

Product

Resources

About