Wei Yan

Structure-based design and synthesis of 3-substituted-1,2,4-triazolo[1,5-a]pyrimidines as dual vinca/gatorbulin-site ligands for cancer treatment

Chufeng Zhang, Wei Yan, Hongxiu Chen, Fang Wang et autres

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Discovery of Highly Selective and Potent Macrocyclic JAK2 Inhibitors for the Treatment of MPNs

Songhui Qin, Rui Wu, Yang Tian, Minghai Tang et autres

Abstract The development of selective JAK2 inhibitors represents a promising therapeutic strategy for MPNs. Building upon the foundation of our first-generation JAK2 inhibitor, we employed macrocyclization-driven structural optimization to address its off-target limitations. This strategy yielded a novel class of macrocyclic JAK2 …

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Discovery of Potent, Specific, and Orally Available NLRP3 Inflammasome Inhibitors Based on Pyridazine Scaffolds for the Treatment of Septic Shock and Peritonitis

Zhiyuan Fu, Yangqin Duan, Heying Pei, Yurong Zou et autres

The NLRP3 inflammasome is a multiprotein complex that is a component of the innate immune system, involved in the production of pro-inflammatory cytokines. Its abnormal activation is associated with many inflammatory diseases. In this study, we designed and synthesized a series of …

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The cytotoxic natural compound erianin binds to colchicine site of β-tubulin and overcomes taxane resistance

Wei Yan, Yongzhao Zhou, Xue Yuan, Peng Bai et autres

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Structure-based design and synthesis of BML284 derivatives: A novel class of colchicine-site noncovalent tubulin degradation agents

Chufeng Zhang, Wei Yan, Yan Liu, Minghai Tang et autres

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Cevipabulin induced abnormal tubulin protofilaments polymerization by binding to Vinblastine site and The Seventh site

Peng Bai, Wei Yan, Jianhong Yang

Microtubules, composed of αβ-tubulin heterodimers, are crucial targets for chemotherapeutic agents and possess eight binding sites. Our previous study identified cevipabulin as the only one agent capable of simultaneously binding to two different sites (Vinblastine site and The Seventh site). Binding to …

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Crystal structure of tubulin-barbigerone complex enables rational design of potent anticancer agents with isoflavone skeleton

Wei Yan, Yong Li, Yan Liu, Yi Wen et autres

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Small Molecules Promote Selective Denaturation and Degradation of Tubulin Heterodimers through a Low-Barrier Hydrogen Bond

Jianhong Yang, Yong Li, Qiang Qiu, Ruihan Wang et autres

Here, we report a novel mechanism to selectively degrade target proteins. 3-(3-Phenoxybenzyl)amino-β-carboline (PAC), a tubulin inhibitor, promotes selective degradation of αβ-tubulin heterodimers. Biochemical studies have revealed that PAC specifically denatures tubulin, making it prone to aggregation that predisposes it to ubiquitinylation and …

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Structure-Based Design and Synthesis of N-Substituted 3-Amino-β-Carboline Derivatives as Potent αβ-Tubulin Degradation Agents

Yong Li, Yan Liu, Zejiang Zhu, Wei Yan et autres

So far, relatively few small molecules have been reported to promote tubulin degradation. Our previous studies have found that compound 2, a noncovalent colchicine-site ligand, was capable of promoting αβ-tubulin degradation. To further improve its antiproliferative activity, 66 derivatives or analogues of …

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Discovery of a Series of Hydroxamic Acid-Based Microtubule Destabilizing Agents with Potent Antitumor Activity

Linyu Yang, Wanhua Zhang, Qiang Qiu, Zhengying Su et autres

Hydroxamic acid group is one of the characteristic pharmacophores of histone deacetylase (HDAC) inhibitors. But here, we discovered a series of hydroxamic acid-based microtubule destabilizing agents (MDAs), which were derived from shortening the length of the linker in HDAC6 inhibitor SKLB-23bb. Interestingly, …

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Design, Synthesis, and Bioactivity Evaluation of Dual-Target Inhibitors of Tubulin and Src Kinase Guided by Crystal Structure

Lun Wang, Yunhua Zheng, Dan Li, Jianhong Yang et autres

Klisyri (KX01) is a dual tubulin/Src protein inhibitor that has shown potential therapeutic effects in several tumor models. However, a phase II clinical trial in patients with bone-metastatic castration-resistant prostate cancer was halted because of lack of efficacy. We previously reported that …

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Cevipabulin-tubulin complex reveals a novel agent binding site on α-tubulin with tubulin degradation effect

Jianhong Yang, Yamei Yu, Yong Li, Wei Yan et autres

Microtubules, composed of αβ-tubulin heterodimers, have remained popular anticancer targets for decades. Six known binding sites on tubulin dimers have been identified thus far, with five sites on β-tubulin and only one site on α-tubulin, hinting that compounds binding to α-tubulin are …

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