The Wnt/β-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis. Wnt signaling is induced, and β-catenin is activated, associated with the development and progression of renal fibrosis. Wnt/β-catenin controls the expression of various downstream mediators such as snail1, twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1, transient receptor potential canonical 6, and renin-angiotensin system components in epithelial cells, fibroblast, and macrophages. In addition, Wnt/β-catenin is usually intertwined with other signaling pathways to promote renal interstitial fibrosis. Actually, given the crucial of Wnt/β-catenin signaling in renal fibrogenesis, blocking this signaling may benefit renal interstitial fibrosis. There are several antagonists of Wnt signaling that negatively control Wnt activation, and these include soluble Fzd-related proteins, the family of Dickkopf 1 proteins, Klotho and Wnt inhibitory factor-1. Furthermore, numerous emerging small-molecule β-catenin inhibitors cannot be ignored to prevent and treat renal fibrosis. Moreover, we reviewed the knowledge focusing on anti-fibrotic effects of natural products commonly used in kidney disease by inhibiting the Wnt/β-catenin signaling pathway. Therefore, in this review, we summarize recent advances in the regulation, downstream targets, role, and mechanisms of Wnt/β-catenin signaling in renal fibrosis pathogenesis. We also discuss the therapeutic potential of targeting this pathway to treat renal fibrosis; this may shed new insights into effective treatment strategies to prevent and treat renal fibrosis.

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Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis.

Novel coumarin-indole derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors targeting the colchicine binding site. Among these compounds, compound MY-413 displayed the most potent inhibitory activities against gastric cancer cell line MGC-803 with an IC50 value of 0.011 μM. Furthermore, the IC50 values of compound MY-413 was less than 0.1 μM for other 17 cancer cell lines and less than 0.05 μM for other 8 cancer cell lines. Compound MY-413 effectively inhibited the tubulin polymerization (IC50 = 2.46 μM) by binding to the colchicine site. Screening for the inhibitory effects of compound MY-413 on 61 kinases, it was found that compound MY-413 could inhibit MAPK pathways-related kinases. Because of the inhibitory effects of compound MY-413 on tubulin polymerization and MAPK signaling pathway, compound MY-413 induced cell apoptosis, arrested the cell cycle in the G2/M phase, induced the inhibition of cell proliferation and migration in gastric cancer cells MGC-803 and HGC-27. In addition, compound MY-413 could significantly inhibit tumor growth in MGC-803 xenograft tumor models with tumor growth inhibition (TGI) rates of 70% (15 mg/kg) and 80% (30 mg/kg) without obvious toxicity. Consistent with the in vitro results, compound MY-413 also inhibited MAPK signaling pathway, and induced apoptosis and proliferation inhibition in vivo. In conclusion, this work indicated that compound MY-413 was a promising lead compound for the further investigation as a potential anti-gastric cancer agent. 

Discovery of novel coumarin-indole derivatives as tubulin polymerization inhibitors with potent anti-gastric cancer activities.

Targeted protein degradation (TPD) provides unprecedented opportunities for drug discovery. While the proteolysis-targeting chimera (PROTAC) technology has already entered clinical trials and changed the landscape of small-molecule drugs, new degrader technologies harnessing alternative degradation machineries, especially lysosomal pathways, have emerged and broadened the spectrum of degradable targets. We have recently proposed the concept of autophagy-tethering compounds (ATTECs) that hijack the autophagy protein microtubule-associated protein 1A/1B light chain 3 (LC3) for targeted degradation. Other groups also reported degrader technologies engaging lysosomal pathways through different mechanisms including AUTACs, AUTOTACs, LYTACs and MoDE-As. In this review, we analyse and discuss ATTECs along with other lysosomal-relevant degrader technologies. Finally, we will briefly summarize the current status of these degrader technologies and envision possible future studies.

Emerging degrader technologies engaging lysosomal pathways

Dual inhibition of tubulin and poly(ADP-ribose) polymerase-1 (PARP-1) may become an attractive approach for cancer therapy. Here, we discover a dual tubulin/PARP-1 inhibitor (termed as TP-3) using structure-based virtual screening. TP-3 shows strong dual inhibitory effects on both tubulin and PARP-1. Cellular assays reveal that TP-3 shows superior antiproliferative activities against human cancer cells, including breast, liver, ovarian, and cervical cancers. Further studies indicate that TP-3 plays an antitumor role through multiple mechanisms, including the disturbance of the microtubule network and the PARP-1 DNA repairing function, accumulation of DNA double-strand breaks, inhibition of the tube formation, and induction of G2/M cell cycle arrest and apoptosis. In vivo assessment indicates that TP-3 inhibits the growth of MDA-MB-231 xenograft tumors in nude mouse with no notable side effects. These data demonstrate that TP-3 is a dual-targeting, high-efficacy, and low-toxic antitumor agent.

Discovery of a Dual Tubulin and Poly(ADP-Ribose) Polymerase-1 Inhibitor by Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, and Biological Evaluation.

https://doi.org/10.1016/j.drudis.2022.05.026

Drug repurposing: An effective strategy to accelerate contemporary drug discovery

Microtubules play a crucial role in multiple cellular functions including mitosis, cell signaling, and organelle trafficking, which makes the microtubule an important target for cancer therapy. Despite the great successes of microtubule-targeting agents in the clinic, the development of drug resistance and dose-limiting toxicity restrict their clinical efficacy. In recent years, multitarget therapy has been considered an effective strategy to achieve higher therapeutic efficacy, in particular dual-target drugs. In terms of the synergetic effect of tubulin and other antitumor agents such as receptor tyrosine kinases inhibitors, histone deacetylases inhibitors, DNA-damaging agents, and topoisomerase inhibitors in combination therapy, designing dual-target tubulin inhibitors is regarded as a promising approach to overcome these limitations and improve therapeutic efficacy. In this Perspective, we discussed rational target combinations, design strategies, structure-activity relationships, and future directions of dual-target tubulin inhibitors.

Recent Progress on Tubulin Inhibitors with Dual Targeting Capabilities for Cancer Therapy.

Developing potent LC3-targeting AUTAC tools for protein degradation with selective autophagy.

https://doi.org/10.1016/j.apsb.2021.12.022

Development of small molecule extracellular signal-regulated kinases (ERKs) inhibitors for cancer therapy

Tyrosinase (EC 1.14.18.1) plays an indispensable role in the rate-limiting steps of melanin biosynthesis, and its uncontrolled activity may result in various diseases, such as albinism, melanoma, freckles, etc. The inhibition of tyrosinase activity may provide a useful and efficient strategy to treat hyperpigmentation disorders. However, the widely used tyrosinase inhibitors, like α-arbutin, hydroquinone, and kojic acid, have many shortcomings, such as lower efficacy and much more side effects. Herein, we reported the use of homology modeling and multistep structure-based virtual screening for the discovery of novel tyrosinase inhibitors. In this study, 10 initial potential hits (compounds T1–T10) were evaluated for enzyme inhibition and kinetic study, with kojic acid being used as a control. Among them, the IC50 values of both T1 (11.56 ± 0.98 μmol/L) and T5 (18.36 ± 0.82 μmol/L) were superior to that of kojic acid (23.12 ± 1.26 μmol/L). Moreover, T1 and T5 were also identified as the effective noncompetitive tyrosinase inhibitors by the subsequent kinetic study. Above all, T1 and T5 may represent the promising drug candidates for hyperpigmentation therapy in pharmaceutical fields, as well as the effective whitening agents in cosmetic applications.

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Faqian Bu

Papers

Recent Progress on Tubulin Inhibitors with Dual Targeting Capabilities for Cancer Therapy.

Developing potent LC3-targeting AUTAC tools for protein degradation with selective autophagy.

Development of small molecule extracellular signal-regulated kinases (ERKs) inhibitors for cancer therapy

Discovery of Tyrosinase Inhibitors: Structure-Based Virtual Screening and Biological Evaluation

Repurposing drugs in autophagy for the treatment of cancer: From bench to bedside.