PROTAC technology as a novel tool to identify the target of lathyrane diterpenoids

Wu, Yanli; Yang, Yueying; Wang, Wang; Sun, Dejuan; Liang, Jing; Zhu, Man; Li, Hua; Chen, Lixia

doi:10.1016/j.apsb.2022.07.007

Cited by 22 publications

(20 citation statements)

References 5 publications

(5 reference statements)

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“…, BRD9). PROTAC is not only an emerging drug discovery modality but also offers new chemical tools for target identification and validation and for deciphering target biology. , For example, PROTAC-mediated degradation can reveal the noncatalytic activity of protein kinases. , Herein, we report the discovery and characterization of XL01126, a von Hippel–Lindau (VHL)-based, fast, potent, cooperative, and selective LRRK2 PROTAC degrader that is also orally bioavailable and blood–brain barrier (BBB)-permeable. XL01126 qualifies as a chemical probe to study LRRK2 biology, further validate the target as a therapeutic concept in PD, and usher in future drug development.…”

Section: Introductionmentioning

confidence: 99%

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2

et al. 2022

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Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most promising targets for Parkinson's Disease. LRRK2 targeting strategies have primarily focused on Type 1 kinase inhibitors, which however have limitations as the inhibited protein can interfere with natural mechanisms which could lead to undesirable side effects. Herein, we report the development of LRRK2 Proteolysis Targeting Chimeras (PROTACs), culminating in the discovery of degrader XL01126, as an alternative LRRK2 targeting strategy. Initial designs and screens of PROTACs based on ligands for E3 ligases von Hippel-Lindau (VHL), Cereblon (CRBN), and cellular inhibitor of Apoptosis (cIAP) identified the best degraders containing thioetherconjugated VHL ligand VH101. A second round of medicinal chemistry exploration led to qualifying XL01126 as a fast and potent degrader of LRRK2 in multiple cell lines, with DC50 values within 15-72 nM, Dmax values range from 82-90%, and degradation half-lives span from 0.6h to 2.4h. XL01126 exhibits high cell permeability and forms a positively cooperative ternary complex with VHL and LRRK2 (α=5.7), which compensates for a substantial loss of binary binding affinities to VHL and LRRK2, underscoring its strong degradation performance in cells. Remarkably, XL01126 is orally bioavailable (F=15%) and can penetrate the blood brain barrier after either oral or parenteral dosing in mice. Taken together, these experiments qualify XL01126 as a suitable degrader probe to study non-catalytic and scaffolding functions of LRRK2 in vitro and in vivo and offer an attractive starting point for future drug development.

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Section: Introductionmentioning

confidence: 99%

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2

et al. 2022

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“…Finally, in addition to their therapeutic properties, natural degraders also have the potential to be developed as potent chemical biology tools not only for protein chemical genetic knockdown, e.g ., two-headed estradiol PROTACs used to deplete the ER, but also for target identification of bioactive compounds, e.g., lathyrane-based PROTACs used to target the MAFF protein . In addition, AUTAC1 ( 102 ) is a paradigm for the application of NPs in new emerging types of TPD technologies .…”

Section: Discussionmentioning

confidence: 99%

“…The designed PROTAC molecule ZCY-PROTAC ( 66 ) used a 3-polyethylene glycol (3-PEG) linker to combine a lathyrol ( 67 ) with a CRBN recruiter thalidomide (Figure ). Through comparative quantitative proteomics, the downregulated POI degraded by the PROTAC was found to be the MAF BZIP transcription factor F (MAFF) protein in both RAW264.7 and HEK293T cells (1–40 μM, 24 h) . The key advantage of this method is different from that of the traditional affinity-based target identification method, as it has a strict requirement for affinity between the targets and small molecules, which is favorable for the moderate activity of NPs.…”

Section: Np-inspired Targeted Protein Degradersmentioning

confidence: 99%

Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

Cai

et al. 2022

J. Med. Chem.

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Targeted protein degradation (TPD), a promising therapeutic strategy in drug discovery, has great potential to regulate the endogenous degradation of undruggable targets with small molecules. As vital resources that provide diverse structural templates for drug discovery, natural products (NPs) are a rising and robust arsenal for the development of therapeutic TPD. The first proof-of-concept study of proteolysis-targeting chimeras (PROTACs) was a natural polyketide ovalicin-derived degrader; since then, NPs have shown great potential to promote TPD technology. The use of NP-inspired targeted protein degraders has been confirmed to be a promising strategy to treat many human conditions, including cancer, inflammation, and nonalcoholic fatty liver disease. Nevertheless, the development of NP-inspired degraders is challenging, and the field is currently in its infancy. In this review, we summarize the bioactivities and mechanisms of NP-inspired degraders and discuss the associated challenges and future opportunities in this field.

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“…In an article in 2020, PROTAC technology was combined with a quantitative proteomic analysis to identify the unknown target of the multikinase inhibitor sorafenib [ 41 ]. Recently, the research team at Shenyang Pharmaceutical University creatively introduced PROTAC technology into the field of traditional Chinese medicine research [ 42 ]. The combination of the PROTAC technique with quantitative proteomics and the molecular interaction detection technique represented by a microscale thermophoresis (MST) assay were proposed.…”

Section: Natural Products and Their Derivatives In Protac Designmentioning

confidence: 99%

Protein-Targeted Degradation Agents Based on Natural Products

Jia

Wang

et al. 2022

Pharmaceuticals

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Natural products are an important source of drug lead compounds, and natural products with significant biological activity are constantly being discovered and used in clinical practice. At present, natural products play an important role in the targeted therapy of cancer, cardiovascular and cerebrovascular diseases, nervous system diseases, and autoimmune diseases. Meanwhile, in recent years, the rise of protein-targeted degradation technologies, such as proteolysis-targeting chimeras (PROTACs) and molecular glues, has provided a new solution for drug resistance caused by clinical molecular-targeting drugs. It is noteworthy that natural products and their derivatives, as important components of PROTACs and molecular glues, play an important role in the development of protein-targeting drugs. Hence, this review summarized the protein-targeted degradation agents based on natural products, such as PROTACs and molecular glues. More natural products with the potential to be used in the development of PROTACs and molecular glues as targeted protein degradation agents are still being investigated.

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PROTAC technology as a novel tool to identify the target of lathyrane diterpenoids

Cited by 22 publications

References 5 publications

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2

Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2

Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

Protein-Targeted Degradation Agents Based on Natural Products

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