A Two-part, Randomized, Double-blind, Multi-center, Placebo-controlled Study of the Dose-range, Safety and Efficacy of 4 and 12 Weeks of Treatment With AP1189 in Adult Rheumatoid Arthritis (RA) Patients With an Inadequate Response to Methotrexate (MTX) Alone - (RESOLVE)

The RESOLVE study is a two-part, randomized, double-blind, multi-center, placebo-controlled study of the safety, dose-range finding confirmation, and efficacy of 4 (Part A) and 12 weeks (Part B) of treatment with AP1189 in adult RA patients with an inadequate response to MTX alone.

开始日期2022-11-30

申办/合作机构

SynAct Pharma ApS

[+1]

NCT05516979 / Completed临床2期

A Double-blind, Multi-center, Randomized, Placebo-controlled Study of the Safety and Efficacy of 12 Weeks Extended Treatment With AP1189 in Early Rheumatoid Arthritis (RA) Patients naïve to DMARD Treatment

The study is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of 12 weeks daily treatment with 100 mg AP1189 in RA patients who are to start up-titration with methotrexate (MTX).

开始日期2022-09-26

申办/合作机构

SynAct Pharma ApS

[+1]

EUCTR2022-001828-15-BG / Not yet recruiting临床2期

A double-blind, multi-center, randomized, placebo-controlled study of the safety and efficacy of 12 weeks extended treatment with AP1189 in early rheumatoid arthritis (RA) patients naïve to DMARD treatment -EXPAND

开始日期2022-09-14

申办/合作机构

SynAct Pharma ApS

100 项与 MC3R x MC1R 相关的临床结果

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100 项与 MC3R x MC1R 相关的转化医学

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0 项与 MC3R x MC1R 相关的专利（医药）

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项与 MC3R x MC1R 相关的文献（医药）

2024-08-01·Neuropeptides

Effects of an herbal adaptogen feed-additive on feeding-related hypothalamic neuropeptides in chronic cyclic heat-stressed chickens

Article

作者: Ardakani, Maryam Afkhami ; Greene, Elizabeth S ; Dridi, Sami

Heat stress (HS) is a global serious issue in the poultry industry with numerous adverse effects, including increased stress, depressed feed intake (FI), poor growth performance and higher mortality. Herbal adaptogens, plant extracts considered as stress response modifiers, are metabolic regulators that improve an organism's ability to adapt to and minimize damage from environmental stresses. Previously, we showed that herbal adaptogen supplementation increased FI and body weight (BW) of broiler (meat-type) chickens reared under HS conditions. Therefore, we hypothesized that these effects may be mediated through modulation of hypothalamic feeding-related neuropeptides. Male Cobb 500 chicks were reared in 12 environmental chambers with three diets: a corn-soybean-based diet (C) and two herbal adaptogen-supplemented diets at 500 g/1000 kg (NR-PHY-500) and 1 kg/1000 kg (NR-PHY-1000). Broilers in 9 chambers were exposed to chronic cyclic HS (35 °C for 8 h/day) from d29 to d42, while 3 chambers were maintained at 24 °C (thermoneutral, TN) for all 42 days. Hypothalamic samples were collected on d42 from each group, both before the onset of HS (Pre-HS) that day and after 3 h of HS (post-HS). Hypothalamic expressions of neuropeptide Y (NPY) receptors Y4 and Y7, Corticotropin-releasing hormone (CRH), orexin receptor 1 (ORXR1), melanocortin receptors (MC1R, MC4R, and MC5R), visfatin and neurosecretory protein GL (NPGL) genes were significantly upregulated by adaptogen supplementation. The hypothalamic expression of MC2R was affect by period, with a significant upregulation during post-HS phase. There was a significant period by treatment interaction for hypothalamic orexin and adiponectin expression. The hypothalamic expression of NPY, Y1, Y2, Y5, Y6, proopiomelanocortin (POMC), cocaine and amphetamine regulated transcript (CART), agouti-related peptide (AgRP), ORXR2, AdipR1/2, MC3R, and ghrelin was not affected by diet supplementation nor by HS exposure. In conclusion, these findings suggest that in-feed supplementation of adaptogen might improve FI and growth via modulation of hypothalamic feeding-related neuropeptides in heat-stressed broilers.

2023-10-17·Analytical chemistry

Label-Free Quantitative Thermal Proteome Profiling Reveals Target Transcription Factors with Activities Modulated by MC3R Signaling.

Article

作者: Nezhyva, Mariya ; Andrén, Per E ; Sandbaumhüter, Friederike A ; Jansson, Erik T

Thermal proteome profiling with label-free quantitation using ion-mobility-enhanced LC-MS offers versatile data sets, providing information on protein differential expression, thermal stability, and the activities of transcription factors. We developed a multidimensional data analysis workflow for label-free quantitative thermal proteome profiling (TPP) experiments that incorporates the aspects of gene set enrichment analysis, differential protein expression analysis, and inference of transcription factor activities from LC-MS data. We applied it to study the signaling processes downstream of melanocortin 3 receptor (MC3R) activation by endogenous agonists derived from the proopiomelanocortin prohormone: ACTH, α-MSH, and γ-MSH. The obtained information was used to map signaling pathways downstream of MC3R and to deduce transcription factors responsible for cellular response to ligand treatment. Using our workflow, we identified differentially expressed proteins and investigated their thermal stability. We found in total 298 proteins with altered thermal stability, resulting from MC3R activation. Out of these, several proteins were transcription factors, indicating them as being downstream target regulators that take part in the MC3R signaling cascade. We found transcription factors CCAR2, DDX21, HMGB2, SRSF7, and TET2 to have altered thermal stability. These apparent target transcription factors within the MC3R signaling cascade play important roles in immune responses. Additionally, we inferred the activities of the transcription factors identified in our data set. This was done with Bayesian statistics using the differential expression data we obtained with label-free quantitative LC-MS. The inferred transcription factor activities were validated in our bioinformatic pipeline by the phosphorylated peptide abundances that we observed, highlighting the importance of post-translational modifications in transcription factor regulation. Our multidimensional data analysis workflow allows for a comprehensive characterization of the signaling processes downstream of MC3R activation. It provides insights into protein differential expression, thermal stability, and activities of key transcription factors. All proteomic data generated in this study are publicly available at DOI: 10.6019/PXD039945.

2023-10-13·ACS Pharmacology & Translational Science

Development of Melanocortin 4 Receptor Agonists by Exploiting Animal-Derived Macrocyclic, Disulfide-Rich Peptide Scaffolds

Article

作者: Kozisek, Xaver ; McCormick, Peter J. ; Farooq, Zara ; Draxler, Claudia ; Gruber, Christian W. ; Craik, David J. ; Aslanoglou, Despoina ; Durek, Thomas ; White, Andrew M. ; Muratspahić, Edin

G protein-coupled receptors are among the most widely studied classes of drug targets. A major challenge in this field is to develop ligands that will selectively modulate a single receptor subtype to overcome the disadvantages of undesired "off target" effects caused by lack of target and thus signaling specificity. In the current study, we explored ligand design for the melanocortin 4 receptor (MC4R) since it is an attractive target for developing antiobesity drugs. Endogenously, the receptor is activated by peptide ligands, i.e., three melanocyte-stimulating hormones (α-MSH, β-MSH, and γ-MSH) and by adrenocorticotropic hormone. Therefore, we utilized a peptide drug design approach, utilizing "molecular grafting" of pharmacophore peptide sequence motifs onto a stable nature-derived peptide scaffold. Specifically, protegrin-4-like-peptide-1 (Pr4LP1) and arenicin-1-like-peptide-1 (Ar3LP1) fully activated MC4R in a functional cAMP assay with potencies of 3.7 and 1.0 nM, respectively. In a nanoluciferase complementation assay with less signal amplification, the designed peptides fully recruited mini-Gs with subnanomolar and nanomolar potencies. Interestingly, these novel peptide MC4R ligands recruited β-arrestin-2 with ∼2-fold greater efficacies and ∼20-fold increased potencies as compared to the endogenous α-MSH. The peptides were inactive at related MC1R and MC3R in a cAMP accumulation assay. These findings highlight the applicability of animal-derived disulfide-rich scaffolds to design pathway and subtype selective MC4R pharmacological probes. In the future, this approach could be exploited to develop functionally selective ligands that could offer safer and more effective obesity drugs.

项与 MC3R x MC1R 相关的新闻（医药）

2023-08-01

·药时代

王明伟/杨德华研究团队成功解析人源黑素皮质素受体3和5复合物的三维结构

2023年8月1日（北京时间），复旦大学基础医学院王明伟团队携手中国科学院上海药物研究所杨德华团队在Cell Discovery在线发表了题为“Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors”的研究论文。该论文首次报道了人源黑素皮质素受体3（Melanocortin-3 receptor, MC3R）结合内源性选择性配体γ-黑色素细胞刺激素（γ-Melanocyte-stimulating hormone, γ-MSH）以及人源黑素皮质素受体5（MC5R）分别结合内源性非选择性配体α-MSH和合成多肽配体PG-901与下游Gs蛋白复合物的冷冻电镜结构，结合大量功能实验数据，不仅系统阐明了内源性配体亚型选择性的结构基础，而且揭示了PG-901激动MC5R但拮抗MC3R的分子机制。黑素皮质素系统是神经–免疫–内分泌轴的重要组成部分，由五种黑素皮质素受体（MC1R-MC5R)、四种黑素皮质素（α-MSH、β-MSH、γ-MSH和ACTH）和两种内源性拮抗剂（Agouti和Agouti-related peptide, AgRP）组成1。五种受体通过与内源性配体结合参与多种生理调控，如MC1R与皮肤色素沉着和免疫反应密切相关；MC2R参与肾上腺皮质激素的生成；MC3R和MC4R是神经系统控制食欲、能量代谢及性功能的关键组成部分，而MC5R与外分泌腺功能高度相关2-5。目前已有多种靶向MCRs的内源性多肽配体类似物用于治疗肥胖症、关节炎、皮肤病和性欲减退等6, 7，如α-MSH类似物布美诺肽（Bremelanotide）和赛美拉肽（Setmelanotide）分别于2019年和2020年获批上市用于治疗绝经前女性性欲减退症和因黑素皮质素原和瘦素受体等基因缺陷导致的肥胖症。然而，由于这五种受体的序列高度保守，使得相关药物的亚型选择性较差，存在皮肤色素沉积、心动过速和血压升高等副作用，限制了临床应用。不久前，王明伟/杨德华团队、中国科学院上海药物研究所徐华强团队和浙江大学医学院张岩团队紧密合作，先后获得了MC1R8、MC2R9和MC4R10的三维结构。在此基础上进一步解析MC3R和MC5R的精细结构将深化人们对这个受体家族的认识。为此，王明伟/杨德华研究团队经过多轮载体筛选和应用NanoBiT系连技术11获得了颗粒均一且性状稳定的MC3R和MC5R蛋白复合物，应用冷冻电镜技术成功解析了分辨率分别为2.86 Å、2.73 Å和2.59 Å的γ-MSH–MC3R–Gs、α-MSH–MC5R–Gs和PG-901–MC5R–Gs三个复合物的立体结构（图1）。图1. γ-MSH–MC3R–Gs、α-MSH–MC5R–Gs和PG-901–MC5R–Gs复合物的冷冻电镜结构。a-b, γ-MSH、α-MSH和PG-901与黑素皮质素受体的作用示意图 (a) 及其氨基酸序列比对 (b)；c-e, γ-MSH–MC3R–Gs (c)、α-MSH–MC5R–Gs (d) 和PG-901–MC5R–Gs (e) 的复合物结构。研究表明，γ-MSH、α-MSH和PG-901均呈“U”形插入受体的正构口袋，其中黑素皮质素高度保守的HFRW基序深入受体跨膜域（Transmembrane domain, TMD），与受体形成了广泛的相互作用。内源性选择性激动剂γ-MSH对MC3R具有最高的激动活性。综合序列比对、结构叠合对比及功能实验结果，研究人员发现γ-MSH的羧基末端和MC3R的异亮氨酸I2656.58（遵循Ballesteros–Weinstein编号规则12）可能是决定γ-MSH亚型选择性的关键因素（图2）。PG-901是MC5R的高活性完全激动剂，却是MC3R的拮抗剂。结构和功能分析显示，3.36（MC5R中为V1263.36，MC3R中为L1283.36）是PG-901激动MC5R和拮抗MC3R的关键位点。此外，研究人员还发现了不同二价金属离子对黑素皮质素受体的cAMP信号通路迥异的调控作用。图2. γ-MSH选择性识别MC3R的分子机制。a, γ-MSH与MC3R相互作用的示意图；b-d, γ-MSH的氨基末端 (b)、HFRW基序 (c) 和羧基末端 (d) 与MC3R相互作用；e, 单点突变对MC3R cAMP信号转导的影响；f, γ-MSH的亚型选择性。复旦大学基础医学院博士研究生冯文博和复旦大学基础医学院青年研究员周庆同为该论文的共同第一作者；复旦大学王明伟讲席教授和中国科学院上海药物研究所杨德华研究员为该论文的共同通讯作者。该研究成果先后获得了国家自然科学基金委员会、国家科学技术部、国家卫生与健康委员会、中国科学院和上海市科学技术委员会等机构的经费资助。全文链接：https://doi.org/10.1038/s41421-023-00586-4（也可后台留邮箱，获取PDF版本）参考文献：1. Yang, Y. & Harmon, C.M. Molecular signatures of human melanocortin receptors for ligand binding and signaling. Biochim Biophys Acta Mol Basis Dis 1863, 2436-2447 (2017).2. van der Kraan, M. et al. Expression of melanocortin-5 receptor in secretory epithelia supports a functional role in exocrine and endocrine glands. Endocrinology 139, 2348-2355 (1998).3. Catania, A., Gatti, S., Colombo, G. & Lipton, J.M. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol Rev 56, 1-29 (2004).4. Moscowitz, A.E. et al. The importance of melanocortin receptors and their agonists in pulmonary disease. Front Med 6, 145 (2019).5. Yeo, G.S.H. et al. The melanocortin pathway and energy homeostasis: from discovery to obesity therapy. Mol Metab 48, 101206 (2021).6. Cai, M. & Hruby, V.J. The melanocortin receptor system: a target for multiple degenerative diseases. Curr Protein Pept Sci 17, 488-496 (2016).7. Montero-Melendez, T., Gobbetti, T., Cooray, S.N., Jonassen, T.E. & Perretti, M. Biased agonism as a novel strategy to harness the proresolving properties of melanocortin receptors without eliciting melanogenic effects. J Immunol 194, 3381-3388 (2015).8. Ma, S. et al. Structural mechanism of calcium-mediated hormone recognition and Gbeta interaction by the human melanocortin-1 receptor. Cell Res 31, 1061-1071 (2021).9. Luo, P. et al. Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1. Cell Res 33, 46-54 (2023).10. Zhang, H. et al. Structural insights into ligand recognition and activation of the melanocortin-4 receptor. Cell Res 31, 1163-1175 (2021).11. Dixon, A.S. et al. NanoLuc complementation reporter optimized for accurate measurement of protein interactions in Cells. ACS Chem Biol 11, 400-408 (2016).12. Ballesteros, J.A. & Weinstein, H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci 25, 366-428 (1995).点击这里，阅读全文！

临床结果临床1期临床研究

2022-06-29

·凯莱英药闻

多肽研发新动态：FDA 接受Endevica黑皮质素-4肽拮抗剂TCMCB07的IND申请，用于癌症和其他慢性疾病患者的恶病质

欢迎关注凯莱英药闻2022年6月28日，Endevica Bio（简称“Endevica”）宣布，FDA接受TCMCB07的新药临床试验申请（IND），用于治疗患有癌症和其他慢性疾病患者的恶病质，公司计划在 2023年第二季度在胰腺癌患者中启动 2 期临床研究。TCMCB07属于黑皮质素-4肽拮抗剂（MC4R），通过抑制下丘脑黑皮质素信号和大脑炎症来降低代谢和能量消耗，在外周给药时可有效穿过血脑屏障，通过提高治疗耐受性和改善生活质量来帮助恶病质患者延长寿命。根据2021年8月公布的临床前数据，在两种原位胰腺癌和头颈癌小鼠恶病质模型中评估TCMCB07皮下给药的结果，显示TCMCB07可使小鼠在癌症恶病质期间保持瘦体重，并减轻肌肉萎缩和体重下降。黑皮质素受体(MCR)参与调节生物体许多生理行为,包括能量平衡、色素沉降、性行为、炎症、心脑血管功能、进食行为、皮脂腺脂肪分泌等等。MCR由刺激腺苷酸环化酶（cAMP）的G蛋白介导。已知五种黑皮质素受体亚型，分别为MC1R、MC2R、MC3R、MC4R以及MC5R。据不完全统计，目前全球在研的MCR药物共28个，如下表：恶病质亦称恶液质，表现为极度消瘦，皮包骨头，形如骷髅，贫血，无力，完全卧床，生活不能自理，极度痛苦，全身衰竭等综合征，由癌症和其他严重慢性病引起。恶病质在约50-80%的晚期癌症患者中普遍存在，也是40%癌症患者死亡的原因。在欧洲，包括醋酸甲地孕酮和醋酸甲羟孕酮在内的孕激素，获批用于治疗癌症和艾滋病相关的恶病质；在日本，2021年1月，口服新型选择性胃饥饿素受体（GHSR）激动剂Adlumiz(anamorelin)获批上市，用于治疗癌症恶病质。Endevica成立于2009 年，旨在创造同类最佳的肽候选药物，根据独有的技术平台对肽进行修饰，以调节血脑屏障后 G 蛋白偶联受体的活性。公司在黑皮质素药效团 (HFRW) 中发现了一个重叠的RFamide 样药效团，它介导了心血管活动，因此开发的黑皮质素没有不良的心血管副作用，在血浆中更稳定，口服活性，PK可预测。目前，公司一项以黑素皮质素为基础治疗药物抑制心血管副作用的美国专利已获批准，相关专利正在申请中。感谢关注、转发，转载授权、加行业交流群，请加管理员微信号“hxsjjf1618"。