作者: Markey, Gary E ; Ryan, Sinéad ; Masterson, Joanne C ; Kellett, Shauna K ; Crue, Taylor ; McKiernan, Susan ; Crowe, Louise ; Conlon, Niall ; Donohoe, Claire L ; Fagan, Olga ; Furuta, Glenn T ; Almeida Cruz, Sofia N

BACKGROUND:

Inflammatory hypoxia is induced by eosinophilic inflammation, while a decreased expression in the key hypoxic regulator, hypoxia-inducible transcription factor (hypoxia-inducible factor-1alpha [HIF-1α]), has been shown in patients with eosinophilic esophagitis (EoE), contributing to maladaptive hypoxic responses in the esophageal epithelium. Recent publications have reported attenuated CD73/ecto-5'-nucleotidase expression in patients with EoE, which is a known extracellular adenosine producing ecto-enzyme and a direct HIF-1α target.

OBJECTIVES:

We sought to check the hypothesis that dysregulated CD73 facilitated epithelial wound healing and barrier dysfunction in EoE and was modulated by HIF-1α and mediated through impaired extracellular adenosine signaling.

METHODS:

In vitro scratch assays and 3-dimensional air-liquid interface cultures were carried out on EPC2-hTERT cells to evaluate wound healing and barrier responses in the esophageal epithelium. Pharmacological CD73 inhibition (α,β-methylene adenosine-5-diphosphate), adenosine receptor A2B (ADORA2B) activation (BAY60-6583), and HIF-1α stabilization (dimethyloxalylglycine) were also used. In vivo, the L2-IL5^OXA, an HIF-1α overexpressing L2-IL5^OXA (L2-IL5⁺/HIF-1A-dPA^+/+/K14Cre⁺)^OXA, and ADORA2B agonist-BAY60-6583 (L2-IL5^OXABAY) EoE mouse models were used.

RESULTS:

Pharmacologic studies demonstrated that CD73 inhibition resulted in defective wound healing responses in scratch assays and decreased epithelial barrier in 3-dimensional air-liquid interface cultures. Activation of downstream ADORA2B signaling improved wound healing responses and barrier functions via restoration of fibronectin (FN1) and occludin (OCLN) expression. In vivo studies in L2-IL5^OXA EoE mouse models recapitulated in vitro findings of improved epithelial barrier integrity characterized by increased expression of occludin following ADORA2B agonism and HIF-1α stabilization.

CONCLUSIONS:

Overall, our study suggests that defective HIF-1α signaling in extended hypoxia is a key driver of CD73 downregulation in EoE, leading to impaired extracellular adenosine signaling, defective wound healing, and barrier dysfunction, establishing the possibility for ADORA2B agonism as a potential novel therapeutic approach for EoE.

2026-02-16·CANCER RESEARCH

Dissection of Gαs and Hedgehog Signaling Cross-talk Reveals Therapeutic Opportunities to Target Hedgehog-Dependent Tumors

Article

作者: Salinas Parra, Natalia ; Mukhopadhyay, Saikat ; Krantz, Sarah ; Sarin, Kavita Y. ; St. Croix, Brad ; Raimondi, Francesco ; Ng, Yeap ; Iglesias-Bartolome, Ramiro ; De Oliveira Rosa, Natalia ; Bell, Braden A. ; Weigert, Roberto ; Lund, Katherine

Abstract:

Basal cell carcinoma (BCC), the most common human cancer, is driven by hyperactivation of the Hedgehog pathway mediated by Smoothened (SMO) signaling and Glioma-Associated Oncogene Homolog (GLI) transcription. Gαs and protein kinase A (PKA) negatively regulate Hedgehog signaling, offering a potential alternative BCC development and treatment pathway. In this study, using histology alongside bulk and single-cell RNA sequencing, we found that mouse BCC–like tumors that originate from Gαs pathway inactivation are highly similar to those driven by canonical Hedgehog signaling induced by constitutive SMO activation. Both pathways led to the expansion of basal stem cells in the skin, with tumor cells clustering in two distinct populations with markers for touch dome and isthmus stem cell–like cells. Interestingly, mutations that reduce Gαs and PKA activity were present in human BCC. Tumors from Gαs pathway inactivation were independent of the canonical Hedgehog regulators SMO and GPR161, establishing them as SMO-independent oncogenic Hedgehog signaling models. Finally, activation of the Gαs-coupled adenosine 2B receptor with BAY60-6583 counteracted oncogenic SMO, reducing Hedgehog signaling and tumor growth. Together, these findings offer a potential therapeutic strategy for BCC.

Significance::

Gαs/PKA pathway inactivation drives Hedgehog-dependent basal cell carcinoma and can be counteracted by activation of the Gαs-coupled adenosine 2B receptor to suppress tumor growth, providing a potential treatment for Hedgehog-driven tumors.

2025-01-23·JOURNAL OF PHYSICAL CHEMISTRY B

Ligand and Residue Free Energy Perturbations Solve the Dual Binding Mode Proposal for an A_2BAR Partial Agonist

Article

作者: Gutiérrez-de-Terán, Hugo ; Tandarić, Tana

Adenosine receptors, particularly A_2BAR, are gaining attention for their role in pathological conditions such as cancer immunotherapy, prompting the exploration for promising therapeutic applications. Despite numerous selective A_2BAR antagonists, the lack of selective full agonists makes the partial agonist BAY60-6583 one of the most interesting activators of this receptor. Recent cryo-EM structures have univocally revealed the binding mode of nonselective ribosidic agonists such as adenosine and its derivative NECA to A_2BAR; however, two independent structures with BAY60-6583 show alternative binding orientations, raising the question of which is the physiologically relevant binding mode. In situations such as this, computational simulations that accurately predict shifts in binding free energy can complement experimental structures. Our study combines QligFEP and QresFEP protocols to directly compare the binding affinity of BAY60-6583 between alternative binding modes as well as providing a direct comparison of in silico mutagenesis studies on each pose with experimental mutational effects. Both methods converge on the experimentally determined binding mode that better explains both the existing SAR and mutagenesis data for this ligand. Our results allow the elucidation of the experimental binding orientation that should be considered as a basis for designing partial agonist derivatives with improved affinity and selectivity and underscore the value of free energy perturbation methods in aiding structure-based drug design.

项与 BAY-60-6583 相关的新闻（医药）

2025-11-28

·百度百家

揭秘人的腺苷A2B受体：结构与药物研发意义

❒ A2BR的功能与研究背景人腺苷A2B受体（A2BR）作为A类G蛋白偶联受体，在人体内发挥着至关重要的作用，涉及多个关键的生理和病理过程。尽管A2BR能够与配体腺苷及NECA结合，但其对这两种配体的识别亲和力相对较低。目前，关于A2BR配体识别及信号传导的详细机制，科学家们仍知之甚少。 2022年12月23日，华东师范大学的宋高洁与上海科技大学的华甜共同在Science Advances期刊上在线发表了一篇题为“Cryo-EM structure of the human adenosine A2B receptor–Gs signaling complex”的研究论文。该研究利用冷冻电子显微镜技术，揭示了人腺苷A2B受体与两种激动剂NECA和BAY60-6583结合时的两种不同结构，这两种结构均与工程化的Gs蛋白偶联。研究显示，这两种结构在正位结合袋上存在细微差异，而这种差异正是导致选择性或特异性的关键原因。此外，研究还发现BAY60-6583具有一个独特的二级口袋，其中的残基V2506.51和N2737.36对A2BR的选择性起到了决定性作用。综上所述，该研究不仅加深了我们对腺苷受体家族配体选择性的理解，还为进一步开发针对相关疾病的A2BR配体提供了宝贵的结构信息。 G蛋白偶联受体（GPCRs）是真核生物中最大且最为多样化的膜蛋白家族，它们普遍具有7个跨膜螺旋束（7TM）的典型结构。这些受体通过细胞膜传递各类信号，从而调控众多生理和病理过程。腺苷，作为一种在哺乳动物体内广泛分布的内源性核苷，能够触发其受体的下游信号，进而对多种关键生理功能进行调节。在腺苷的四种受体中，腺苷A2B受体因其独特的结构和功能而备受关注。腺苷A2A受体（A2AR）和腺苷A2B受体（A2BR）最初被发现与Gs/olf蛋白存在相互作用。1R和A3R通过与Gi/o亚型相互作用来发挥其抑制作用。而近期的研究还揭示，A2BR同样与Gi亚型存在偶联关系。这一发现，加之腺苷受体在体内各部位的广泛分布及其在调控基础生理功能方面的关键作用，使得这些受体成为潜在的药物靶点，可用于治疗多种病理疾病。在过去数十年间，针对腺苷受体的研究已成为药物研发领域的热点。2AR作为腺苷受体的一个重要亚型，一直备受瞩目。其晶体结构在2008年得到了首次解析，这一里程碑式的研究成果为深入探究2AR的结构与功能奠定了坚实基础。此后，针对2AR的研究持续成为科研领域的热点，不仅揭示了其在细胞信号转导中的关键作用，还为其在药物研发中的应用提供了有力支持。 2AR被视为GPCR超家族中的代表性受体，其结构已通过结晶学和冷冻电镜技术得以阐明，从而揭示了与不同类型配体结合时的非活性、中间活性和全活性构象。2BR的非活性与活性状态下的结构至今尚未被明确揭示。 ❒ 研究揭示的结构细节与意义 A2BR-NECA-Gs与A2BR-BAY60-6583-Gs的整体结构（图源自Science Advances）显示出，相较于其他三种腺苷受体，A2BR对腺苷及其衍生物5' - N -乙基羧酰胺腺苷（NECA）的亲和力相对较弱。这一发现为进一步探讨A2BR在病理条件下的作用提供了新的视角。 A2BR的表达显著上调，同时细胞外腺苷浓度也显著增加。这一观察结果提示我们，A2BR在某种病理条件下可能发挥着重要作用。A2BR在糖代谢、血管生成诱导、肿瘤生长、肠道炎症以及心肌缺血等众多生理病理过程中都扮演着关键角色。此外，越来越多的研究显示，这一受体与急性肺损伤和肾损伤的发生也存在密切关联。 A2BR能够触发多种细胞内信号的激活，进而展现出与A不同的生物学效应。针对A2BR的主要激动剂BAY60-6583，已有研究探索其在动脉粥样硬化及心脏疾病治疗方面的应用。2BR拮抗剂PBF-1129在肿瘤免疫治疗的临床试验中正接受评估。同时，研究人员也在探索NECA与BAY60-6583在A2BR上的不同亲和力和作用效果。 ❒ 腺苷受体在药物研发中的地位与应用在探索A2BR的选择性机制时，研究人员利用工程三聚体Gs蛋白，测定了A2BR与NECA和BAY60-6583结合的两个冷冻电镜结构。这些结构与细胞分析结果相互印证，共同揭示了腺苷受体家族在配体识别方面的独特性和多样性。通过这些研究，我们能够更深入地了解腺苷受体的功能及其在肿瘤免疫治疗中的潜在应用。这一研究不仅是对A2BR选择性机制的进一步补充，还揭示了A2BR激动剂BAY60-6583在特异性方面的关键决定因素。这些发现为未来探索更高效的A2BR激动剂提供了重要的理论依据。A2BR配体在疾病治疗方面的应用为相关研究指明了新的方向。

100 项与 BAY-60-6583 相关的药物交易

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