Targeted Protein Degradation: Principles, Strategies, and Applications

He, Tengbing; Wen, Chenxi; Yang, Guodong; Yang, Xuekang

doi:10.1002/adbi.202300083

Cited by 3 publications

(1 citation statement)

References 151 publications

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“…The target protein degradation strategies such as PROTAC and AUTAC have become a new trend in drug development. 27 Different from the traditional small-molecular inhibitors, PROTACs can potentially play a catalytic role by facilitating multiple rounds of degradation of the target protein, thus efficiently improving the inhibitory potency. 28 It has been reported that PROTACs were developed to target multiple targets to degrade the targets simultaneously.…”

Section: ■ Discussionmentioning

confidence: 99%

Design and Synthesis of Dual-Target Inhibitors Targeting Androgen Receptors and Glucocorticoid Receptors to Overcome Antiandrogen Resistance in Castration-Resistant Prostate Cancer

Li,

Han,

Yan

et al. 2024

J. Med. Chem.

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Androgen receptor (AR) antagonists play important roles in the treatment of castration-resistant prostate cancer (CRPC). The glucocorticoid receptor (GR) upregulation leads to drug resistance for clinically used antiandrogens. Therefore, blocking AR/GR signaling simultaneously has become an efficient strategy to overcome the drug resistance of CRPC. Our previous work indicated that Z19 could inhibit the activity of both AR and GR. Herein, we optimized the structure of Z19 and identified GA32 as a potent AR/GR dual inhibitor. GA32 efficiently reduced the mRNA and protein levels of AR/GR downstream genes. GA32 efficiently inhibited the proliferation of enzalutamide resistance CRPC both in vitro and in vivo. GA32 could directly bind to AR and GR, and the predicted binding modes for GA32 with AR/GR suggested that GA32 binds to the AR or GR hormone binding pocket. This work provides a potential lead compound with dual AR/GR inhibitory activity to conquer the drug resistance of CRPC.

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Section: ■ Discussionmentioning

confidence: 99%

Design and Synthesis of Dual-Target Inhibitors Targeting Androgen Receptors and Glucocorticoid Receptors to Overcome Antiandrogen Resistance in Castration-Resistant Prostate Cancer

Li,

Han,

Yan

et al. 2024

J. Med. Chem.

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Acetyl-CoA Carboxylase Proteolysis-Targeting Chimeras: Conceptual Design and Application as Insecticides

Xu,

Feng,

et al. 2024

J. Agric. Food Chem.

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Novel approaches for pest control are essential to ensure a sufficient food supply for the growing global population. The development of new insecticides must meet rigorous regulatory requirements for safety and address the resistance issues of existing insecticides. Proteolysis-targeting chimeras (PROTACs), originally developed for human diseases, show promise in agriculture. They offer innovative insecticides tailored to overcome resistance, opening avenues for agricultural applications. In this study, we developed small-molecule degraders by incorporating pomalidomide as an E3 ligand. These degraders were linked to a ligand (spirotetratmat enol) targeting the ACC protein through a flexible chain, aiming to achieve the efficient control of insects. Compounds 9a–9d were designed, synthesized, and evaluated for biological activities and mechanisms. Among them, 9b exhibited superior potency against Aphis craccivora (LC50 = 107.8 μg mL–1) compared to others and effectively degraded ACC proteins through the ubiquitin-proteasome system. These findings highlight the potential of utilizing PROTAC-based approaches in the development of insecticides for efficient pest control.

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Cryptotanshinone Alleviates Ischemic Retinopathy by Targeting Mitochondrial DNA- STING-NF-κB Axis-Mediated Microglia Activation

Qiu,

Zheng,

Wang

et al. 2024

Preprint

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Pathological retinal angiogenesis is a major cause of vision impairment and blindness. The development of pathological angiogenesis in ischemic retinopathy is linked to oxidative stress and dysregulated inflammatory response, in which microglia play a vital role. Cryptotanshinone (CTS), a bioactive compound found in Salvia miltiorrhiza, demonstrates protective characteristics such as antioxidant and anti-inflammatory properties. Therefore, it might influence abnormal retinal angiogenesis, the pathophysiological mechanisms of which are yet not well known. Overactivation of the stimulator of interferon genes (STING), a DNA-sensing adaptor protein, in microglia is a critical mechanism in ischemic retinopathy. Here, we showed that CTS treatment substantially reduced microglial activation and pathological retinal angiogenesis in a mouse model of oxygen-induced retinopathy (OIR). The integration of network pharmacology, bulk RNA sequencing, single-cell RNA sequencing analyses, and verifying experiments revealed a strong association between the suppression of the STING pathway in microglia and the protective effect of CTS on ischemic retinopathy. Mechanistically, firstly, CTS suppressed the release of cytosolic mitochondrial DNA (mtDNA), a causative factor for STING activation, by suppressing mitochondrial ROS-induced mitochondrial damage. Secondly, CTS inhibited STING’s translocation from the ER to the Golgi and subsequent activation of the downstream TBK1-NF-κB pathway by binding to its Ser162 site. Finally, CTS accelerated lysosome-mediated STING protein degradation by improving lysosomal function. Intriguingly, the inhibitory effects of CTS on microglial activation and retinal neovascularization were eliminated by STING activation. Furthermore, CTS treatment did not provide further protection in Sting deficient (Sting−/−) OIR mice. Collectively, our study indicated that CTS, a natural inhibitor of STING, alleviated ischemic retinopathy by inhibiting the mtDNA-STING-NF-κB signaling pathway via multifaceted mechanisms in microglia.

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Targeted Protein Degradation: Principles, Strategies, and Applications

Cited by 3 publications

References 151 publications

Design and Synthesis of Dual-Target Inhibitors Targeting Androgen Receptors and Glucocorticoid Receptors to Overcome Antiandrogen Resistance in Castration-Resistant Prostate Cancer

Design and Synthesis of Dual-Target Inhibitors Targeting Androgen Receptors and Glucocorticoid Receptors to Overcome Antiandrogen Resistance in Castration-Resistant Prostate Cancer

Acetyl-CoA Carboxylase Proteolysis-Targeting Chimeras: Conceptual Design and Application as Insecticides

Cryptotanshinone Alleviates Ischemic Retinopathy by Targeting Mitochondrial DNA- STING-NF-κB Axis-Mediated Microglia Activation

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