Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope

Ma, Sinan; Ji, Jian-Ai; Tong, Yuanyuan; Zhu, Yuxuan; Dou, Junwei; Zhang, Xian; Xu, Shicheng; Zhu, Tianbao; Xu, Xiu; You, Qidong; Jiang, Zhengyu

doi:10.1016/j.apsb.2022.02.022

Cited by 21 publications

(13 citation statements)

References 180 publications

(213 reference statements)

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“…Proteolysis-targeting chimeras (PROTACs) have emerged as a novel therapeutic strategy in drug discovery, which induce the degradation of pathogenic target proteins through hijacking the ubiquitin-proteasome system in living cells. − PROTACs are heterobifunctional molecules consisting of three moieties: a ligand that binds a protein of interest, another ligand that recruits an E3 ubiquitin ligase, and a linker that concatenates the two ligands. , According to the principles and mechanisms, researchers have made considerable efforts to develop PROTAC-based PD-L1 degraders.…”

Section: Degraders That Bind To Pd-l1mentioning

confidence: 99%

Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway

Wang,

Yuan,

Liao

et al. 2024

J. Med. Chem.

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Targeting the programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway has evolved into one of the most promising strategies for tumor immunotherapy. Thus far, multiple monoclonal antibody drugs have been approved for treating a variety of tumors, while the development of small-molecule PD-1/PD-L1 inhibitors has lagged far behind, with only a few small-molecule inhibitors entering clinical trials. In addition to antibody drugs and small-molecule inhibitors, reducing the expression levels of PD-L1 has attracted extensive research interest as another promising strategy to target the PD-1/PD-L1 pathway. Herein, we analyze the structures and mechanisms of molecules that reduce PD-L1 expression and classify them as degraders and downregulators according to whether they directly bind to PD-L1. Moreover, we discuss the potential prospects for developing PD-L1-targeting drugs based on these molecules. It is hoped that this perspective will provide profound insights into the discovery of potent antitumor immunity drugs. ■ SIGNIFICANCEReducing PD-L1 expression has been considered as a promising strategy to modulate the PD-1/PD-L1 pathway, which has attracted continuous research interests. This perspective focuses on analyzing the molecules capable of reducing PD-L1 expression and classifies them as degraders and down-regulators according to whether they directly bind to PD-L1. Additionally, it provides deep insights into the rational design strategies and challenges for the development of PD-L1 degraders as well as PD-L1-based combination therapies and multitarget drugs.

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Section: Degraders That Bind To Pd-l1mentioning

confidence: 99%

Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway

Wang,

Yuan,

Liao

et al. 2024

J. Med. Chem.

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“…Inspired by the concept of antibody–drug conjugates (ADCs), antibody–PROTACs (Ab–PROTACs) represent a new direction for improving the tissue selectivity and avoiding side effects in normal cells of PROTACs . The Ab–PROTACs can also improve the PK properties of traditional PROTACs by providing an intravenous dosing option and reducing the amount of administration for clinical trials.…”

Section: Discovery Of the Emerging Types Of Protacsmentioning

confidence: 99%

“…The anticancer activity was also consistent with the expression of FOLR1 with an IC 50 of 246 nM toward HeLa cells (high FOLR1 expression) and >10 μM toward HFF-1 cells (low FOLR1 expression). Lower sensitivity for the degradation of compound 34 was demonstrated in the cells with FOLR1 knockdown or in normal cells (MCF10A), and low FOLR1 expressed cancer 51 The Ab− PROTACs can also improve the PK properties of traditional PROTACs by providing an intravenous dosing option and reducing the amount of administration for clinical trials. In principle, Ab−PROTACs are trivalent macromolecules for recognizing different antigens, which are generated by linking a conventional PROTAC, a cleavable linker, and a specific antibody.…”

Section: Discovery Of the Emerging Types Of Protacsmentioning

confidence: 99%

Homobivalent, Trivalent, and Covalent PROTACs: Emerging Strategies for Protein Degradation

Yan

Miao

et al. 2022

J. Med. Chem.

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Proteolysis-targeting chimeras (PROTACs) is a fast-growing technology providing many strengths over inhibition of protein activity directly and is attracting increasing interest in new drug discovery and development. However, efficiently identifying potent and drug-like degraders is still challenging in the development of PROTACs. Complementary to traditional PROTACs, several emerging types of PROTACs, such as homobivalent PROTACs based on two E3 ligases (e.g., CRBN, VHL, MDM2, TRIM24), chemical-or biologicalbased trivalent/multitargeted PROTACs, and covalent PROTACs, are rising for targeted protein degradation. These new types of PROTACs have several advantages over the traditional PROTACs including high selectivity, low toxicity, better therapeutic effects, and so on. In this perspective, we will summarize the latest development of representative PROTACs focusing on research mainly in past 10 years and discuss their advantages and disadvantages. Moreover, the outlook and perspectives on the associated challenges and future directions will be provided.

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“…To address these shortcomings, nonsmall molecule PROTACs such as peptide PROTACs, nucleic acid PROTACs, and antibody PROTACs have emerged in recent years. 9 PROTACs using peptide-based ligands that bind to the surfaces of target proteins are easier to design than small molecule-based PROTACs; 10 in fact, many proteins that cannot be targeted by small molecules can be degraded by peptide PROTACs. An alternative approach is to use nucleic acids as warheads for binding a POI.…”

mentioning

confidence: 99%

“…However, some disadvantages of PROTAC-induced targeted protein degradation (TPD) include insufficiency of available ligand against a POI and difficulty in synthesis. To address these shortcomings, non-small molecule PROTACs such as peptide PROTACs, nucleic acid PROTACs, and antibody PROTACs have emerged in recent years . PROTACs using peptide-based ligands that bind to the surfaces of target proteins are easier to design than small molecule-based PROTACs; in fact, many proteins that cannot be targeted by small molecules can be degraded by peptide PROTACs. − …”

mentioning

confidence: 99%

Development of DNA Aptamer-Based PROTACs That Degrade the Estrogen Receptor

Tsujimura

Naganuma

Ohoka

et al. 2023

ACS Med. Chem. Lett.

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Targeted protein degradation (TPD), using chimeric molecules such as proteolysis-targeting chimeras (PROTACs), has attracted attention as a strategy for selective degradation of intracellular proteins by hijacking the ubiquitin-proteasome system (UPS). However, it is often difficult to develop such degraders due to the absence of appropriate ligands for target proteins. In targeting proteins for degradation, the application of nucleic acid aptamers is considered to be effective because these can be explored using systematic evolution of ligand by exponential enrichment (SELEX) methods. In this study, we constructed chimeric molecules in which nucleic acid aptamers capable of binding to the estrogen receptor α (ERα) and E3 ubiquitin ligase ligands were linked via a linker. ERα aptamer-based PROTACs were found to degrade ERα via the UPS. These findings represent the development of novel aptamer-based PROTACs that target intracellular proteins and are potentially applicable to other proteins.

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Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope

Cited by 21 publications

References 180 publications

Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway

Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway

Homobivalent, Trivalent, and Covalent PROTACs: Emerging Strategies for Protein Degradation

Development of DNA Aptamer-Based PROTACs That Degrade the Estrogen Receptor

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