Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

Burke, M. Desmond; Smith, Alexis R.; Zheng, Guangrong

doi:10.3389/fcell.2022.872729

Cited by 50 publications

(46 citation statements)

References 160 publications

(201 reference statements)

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“…This is mainly due to their event-driven pharmacology, resulting in catalytic removal of POI in its entirety and in degradation driven by binding rather than function disruption. 39 However, acquired resistance to PROTACs by genomic alterations of E3 ligase complex core components cannot be ruled out. 40 Moreover, and more importantly, PROTACs can expand the number of “druggable” targets since they have been demonstrated to degrade proteins lacking a catalytic site or a small-molecule binding site.…”

Section: The Essential Pharmacology Of Protacsmentioning

confidence: 99%

“…In addition, PROTACs can better circumvent some inhibitor resistance mechanisms typical of cancer and infectious diseases, including (i) point mutations, (ii) gain of scaffolding function, and (iii) target protein overexpression. This is mainly due to their event-driven pharmacology, resulting in catalytic removal of POI in its entirety and in degradation driven by binding rather than function disruption . However, acquired resistance to PROTACs by genomic alterations of E3 ligase complex core components cannot be ruled out .…”

Section: The Essential Pharmacology Of Protacsmentioning

confidence: 99%

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Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One

et al. 2022

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Proteolysis targeting chimera (PROTAC)-mediated protein degradation has prompted a radical rethink and is at a crucial stage in driving a drug discovery transition. To fully harness the potential of this technology, a growing paradigm toward enriching PROTACs with other therapeutic modalities has been proposed. Could researchers successfully combine two modalities to yield multifunctional PROTACs with an expanded profile? In this Perspective, we try to answer this question. We discuss how this possibility encompasses different approaches, leading to multitarget PROTACs, light-controllable PROTACs, PROTAC conjugates , and macrocycle- and oligonucleotide-based PROTACs. This possibility promises to further enhance PROTAC efficacy and selectivity, minimize side effects, and hit undruggable targets. While PROTACs have reached the clinical investigation stage, additional steps must be taken toward the translational development of multifunctional PROTACs. A deeper and detailed understanding of the most critical challenges is required to fully exploit these opportunities and decisively enrich the PROTAC toolbox.

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Section: The Essential Pharmacology Of Protacsmentioning

confidence: 99%

Section: The Essential Pharmacology Of Protacsmentioning

confidence: 99%

Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One

et al. 2022

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“…The continued demonstration of ILK as a validated therapeutic target and the demonstration of its kinase activity warrants a greater effort in identifying and developing potent "druggable" compounds to inhibit ILK activity. In addition to such compounds having direct effects on ILK activity and downstream signaling, they could also be useful as critical agents for the development of targeted degradation of ILK through the proteolysis targeting chimera (PROTAC) technology platform [90], offering alternative strategies to target this important protein.…”

Section: Outstanding Questionsmentioning

confidence: 99%

New Perspectives on the Role of Integrin-Linked Kinase (ILK) Signaling in Cancer Metastasis

McDonald¹,

Dedhar

2022

Cancers

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Cancer metastasis is a major barrier to the long-term survival of cancer patients. In cancer cells, integrin engagement downstream of cell-extracellular matrix (ECM) interactions results in the recruitment of cytoskeletal and signaling molecules to form multi-protein complexes to promote processes critical for metastasis. One of the major functional components of these complexes is Integrin Linked Kinase (ILK). Here, we discuss recent advances in our understanding of the importance of ILK as a signaling effector in processes linked to tumor progression and metastasis. New mechanistic insights as to the role of ILK in cellular plasticity, epithelial mesenchymal transition (EMT), migration, and invasion, including the impact of ILK on the formation of invadopodia, filopodia-like protrusions (FLPs), and Neutrophil Extracellular Trap (NET)-induced motility are highlighted. Recent findings detailing the contribution of ILK to therapeutic resistance and the importance of ILK as a potentially therapeutically tractable vulnerability in both solid tumors and hematologic malignancies are discussed. Indeed, pharmacologic inhibition of ILK activity using specific small molecule inhibitors is effective in curtailing the contribution of ILK to these processes, potentially offering a novel therapeutic avenue for inhibiting critical steps in the metastatic cascade leading to reduced drug resistance and increased therapeutic efficacy.

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“…One of the advantages of PROTAC is in overcoming some of the resistance mechanisms to traditional targeted therapies ( Burke et al, 2022 ), represented by AR PROTAC ARV-110 to address metastatic castration-resistant prostate cancer (mCRPC) ( Salami and Crews 2017 ; Halford, 2021 ; Mullard 2021 ). Acquired drug resistance quite often occurs during the use of clinical small molecule inhibitors or antagonists, such as T790M and C797S mutation of EGFR conferred drug resistance induced by EGFR inhibitors ( Thress et al, 2015 ).…”

Section: Drug Resistance In Targeted Protein Degradationmentioning

confidence: 99%

Key Considerations in Targeted Protein Degradation Drug Discovery and Development

Qin¹,

Dai

Wang

2022

Front. Chem.

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Targeting proteins’ enzymatic functions with small molecule inhibitors, as well as functions of receptor proteins with small-molecule agonists and antagonists, were the major forms of small-molecule drug development. These small-molecule modulators are based on a conventional occupancy-driven pharmacological approach. For proteome space traditionally considered undruggable by small-molecule modulators, such as enzymes with scaffolding functions, transcription factors, and proteins that lack well-defined binding pockets for small molecules, targeted protein degraders offer the opportunity to drug the proteome with an event-driven pharmacological approach. A degrader molecule, either PROTAC or molecular glue, brings the protein of interest (POI) and E3 ubiquitin ligase in close proximity and engages the ubiquitin-proteasome system (UPS), the cellular waste disposal system for the degradation of the POI. For the development of targeted protein degraders to meet therapeutic needs, several aspects will be considered, namely, the selective degradation of disease-causing proteins, the oral bioavailability of degraders beyond Lipinski’s rule of five (bRo5) scope, demands of new E3 ubiquitin ligases and molecular glue degraders, and drug resistance of the new drug modality. This review will illustrate several under-discussed key considerations in targeted protein degradation drug discovery and development: 1) the contributing factors for the selectivity of PROTAC molecules and the design of PROTACs to selectively degrade synergistic pathological proteins; 2) assay development in combination with a multi-omics approach for the identification of new E3 ligases and their corresponding ligands, as well as molecular glue degraders; 3) a molecular design to improve the oral bioavailability of bRo5 PROTACs, and 4) drug resistance of degraders.

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Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

Cited by 50 publications

References 160 publications

Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One

Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One

New Perspectives on the Role of Integrin-Linked Kinase (ILK) Signaling in Cancer Metastasis

Key Considerations in Targeted Protein Degradation Drug Discovery and Development

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