This is a multicenter, intra-subject dose-titration open-label study of nevanimibe hydrochloride (HCl) for the treatment of classic congenital adrenal hyperplasia (CAH). Following a Screening Period of approximately 2-14 weeks, eligible subjects will enter a Baseline Period of approximately 2-8 weeks and then a 16-week Treatment Period. It is anticipated that the overall duration of the study per subject will range from 24-42 weeks.

开始日期2018-07-11

申办/合作机构

Millendo Therapeutics US, Inc.

EUCTR2016-002240-17-GB / Not yet recruiting临床2期

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of ATR-101 for the Treatment of Cushing’s Syndrome

开始日期2017-05-16

申办/合作机构

Millendo Therapeutics, Inc.

100 项与 Nevanimibe 相关的临床结果

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100 项与 Nevanimibe 相关的转化医学

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100 项与 Nevanimibe 相关的专利（医药）

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项与 Nevanimibe 相关的文献（医药）

2024-12-01·MOLECULAR AND CELLULAR ENDOCRINOLOGY

The impact of acyl-CoA:cholesterol transferase (ACAT) inhibitors on biophysical membrane properties depends on membrane lipid composition

Article

作者: Reinholdt, Peter ; Müller, Peter ; Akkerman, Vibeke ; Scheidt, Holger A. ; Kongsted, Jacob ; To, Huong ; Wüstner, Daniel ; Luck, Meike ; Scheidt, Holger A ; Kroiss, Matthias ; Lauritsen, Line ; Bashawat, Mohammad

Acyl-coenzyme A: cholesterol acyltransferases are enzymes which are involved in the homeostasis of cholesterol. Impaired enzyme activity is associated with the occurrence of various diseases like Alzheimer's disease, atherosclerosis, and cancers. At present, mitotane is the only inhibitor of this class of enzymes in clinical use for the treatment of adrenocortical carcinoma but associated with common and severe adverse effects. The therapeutic effect of mitotane depends on its interaction with cellular membranes. The search for less toxic but equally effective compounds is hampered by an incomplete understanding of these biophysical properties. In the present study, the interaction of the three ACAT inhibitors nevanimibe, Sandoz 58-035, and AZD 3988 with membranes has been investigated using lipid model membranes in conjunction with biophysical experimental (NMR, ESR, fluorescence) and theoretical (MD simulations) approaches. The data show, that the drugs (i) incorporate into lipid membranes, (ii) differently influence the structure of lipid membranes; (iii) affect membrane structure depending on the lipid composition; and (iv) do not cause hemolysis of red blood cells. The results are discussed with regard to the use of the drugs, in particular to better understand their efficacy and possible side effects.

2021-12-01·Structure (London, England : 1993)2区 · 生物学

Molecular structures of human ACAT2 disclose mechanism for selective inhibition

2区 · 生物学

Article

作者: Long, Tao ; Liu, Yang ; Li, Xiaochun

Endoplasmic reticulum-localized acyl-CoA:cholesterol acyltransferases (ACAT), including ACAT1 and ACAT2, convert cholesterol to cholesteryl esters that become incorporated into lipoproteins or stored in cytosolic lipid droplets. Selective inhibition of ACAT2 has been shown to considerably attenuate hypercholesterolemia and atherosclerosis in mice. Here, we report cryogenic electron microscopy structures of human ACAT2 bound to its specific inhibitor pyripyropene A or the general ACAT inhibitor nevanimibe. Structural analysis reveals that ACAT2 has a topology in membranes similar to that of ACAT1. A catalytic core with an entry site occupied by a cholesterol molecule and another site for allosteric activation of ACAT2 is observed in these structures. Enzymatic assays show that mutations within sites of cholesterol entry or allosteric activation attenuate ACAT2 activity in vitro. Together, these results reveal mechanisms for ACAT2-mediated esterification of cholesterol, providing a blueprint to design new ACAT2 inhibitors for use in the prevention of cardiovascular disease.

2021-06-01·Current opinion in endocrinology, diabetes, and obesity3区 · 医学

Clinical outcomes in 21-hydroxylase deficiency

3区 · 医学

Review

作者: Lajic, Svetlana ; Falhammar, Henrik ; Nordenström, Anna

Purpose of review:

The introduction of synthetic glucocorticoids 70 years ago made survival possible in classic 21-hydroxylase deficiency (21OHD). The currently used glucocorticoid therapy may lead to unphysiological dosing with negative consequencies on health in addition to the problems that may arise due to androgen over-exposure.

Recent findings:

Fertility in females with 21OHD seemed to be impaired, especially in the salt-wasting (SW) phenotype but when pregnancies did occur there was a higher risk for gestational diabetes and cesearean section. Increased fat mass, body mass index, insulin resistance and frequency of autoimmune disorders as well as impaired echocardiographic parameters and lower bone mineral density were found in 21OHD compared to controls. Negative effects on cognitive functions have been identified. Adrenal tumors, especially myelolipomas, were prevalent. Increased knowledge on steroid metabolism in 21OHD and urine steroid profiling may improve assessment of treatment efficacy. Nevanimibe, abiraterone acetate and anastrozole may have a place in the future management of 21OHD. Long-acting glucocorticoids may be a less favorable, especially dexamethasone.

Summary:

The various clinical outcomes need regular monitoring. Negative consequencies are to large extent the result of the unphysiological glucocorticoid replacement. Modern management with improved follow-up and future addition of new drugs may improve outcomes.

项与 Nevanimibe 相关的新闻（医药）

2024-08-29

·生物探索

Cell | 李晓淳研究组揭示磷脂酰丝氨酸合成及其抑制从而促进LDL吸收的分子机制

引言磷脂酰丝氨酸（PS）是细胞膜中最丰富的带负电荷的磷脂，在细胞膜结构、细胞凋亡、血液凝固和病毒感染等生理过程中发挥关键作用。在哺乳动物细胞中，PS的生合成发生在内质网中，磷脂酰丝氨酸合成酶（包括PSS1和PSS2）通过钙离子依赖的方式利用丝氨酸将磷脂酰胆碱（PC）或磷脂酰乙醇胺（PE）的极性头基替换，生成PS【1】。PSS1的功能获得性突变会显著增加PS的产量，并引起名为Lenz-Majewski综合症（LMS）的罕见遗传病，其特征包括智力障碍和骨骼发育不良【2】。最新研究表明，PSS1特异性抑制剂在PTDSS2缺乏的癌症和B细胞淋巴瘤的治疗中显示出潜在的应用价值【3,4】。低密度脂肪蛋白（LDL）通常被称做“坏”胆固醇，LDL在血液中的积累会引发心脑血管疾病和中风。目前，关于治疗高血脂的药物主要作用在增加细胞表面的LDL受体，提高LDL的吸收来减少其在血液中的积累。2020年，1985年诺贝尔奖生理学或医学奖得主Mike Brown 和Joe Goldstein的研究组发现PSS1调控LDL中的胆固醇从细胞膜转运至内质网的过程，其缺失会导致胆固醇在细胞膜上的积累【5,6】。关于PSS1催化PS合成的分子机制、特异性抑制剂的作用机制以及其在LDL代谢调控中的作用仍然不明确。 2024年8月28日，美国德州大学西南医学中心李晓淳研究组在Cell杂志上发表了题为Molecular insights into Human phosphatidylserine synthases 1 reveal its inhibition promotes LDL uptake的研究论文。该研究首次报告了人源PSS1的2.7 Å分辨率的冷冻电镜结构。 PSS1包含10个跨膜螺旋呈现出此前未报道过的拓扑结构。其第1至3和9个跨膜螺旋参与形成二聚化界面，第4至8个跨膜螺旋在内质网腔内侧参与形成催化活性中心，并在其中观察到了内源的底物PE和钙离子。此外，在活性中心的另一侧观察到了两个PS的结合位点，这些位点与LMS致病性功能获得性突变（L265P和P269S）相关。功能研究和分子动力学模拟表明，PS通过变构调节的方式抑制PSS1的催化活性。通过对突变体P269S的结构分析表明，在无PS结合的情况下，PSS1会发生构象变化使得底物磷脂和丝氨酸更容易进入催化活性中心。进一步功能研究表明PSS1利用催化残基组氨酸来激活被钙离子稳定的丝氨酸来完成磷脂头的交换反应。这个反应机理与其研究组发现的MBOAT家族的催化机制类似【7,8】。通过对PSS1与其特异性抑制剂DS55980254复合物结构的解析，作者观察到抑制剂结合在催化中心旁边的口袋。序列比对分析和分子模拟等实验阐明了抑制剂的特异性和与PS类似的变构调节机理。他们的研究进一步揭示，PSS1缺失会导致内质网胆固醇浓度下降，导致SREBP-2途径的激活。细胞实验表明PSS1抑制剂能够显著提高细胞表面LDLR的数量，从而促进LDL的摄取。与目前广泛应用于临床的他汀类药物不同，DS55980254不会抑制胆固醇合成酶羟甲基戊二酸单酰辅酶A（HMGCR）的活性，也不会导致HMGCR在内质网的积累，有可能避免他汀药物所产生的副作用。由于细胞中还广泛存在PSS2，特异性抑制PSS1的活性也不会导致细胞因PS缺失而死亡。这些发现阐述了通过调控磷脂代谢来控制胆固醇吸收的概念，为开发新型降胆固醇药物提供了理论依据。模式图（Credit: Cell）参考文献 1. J. E. Vance, Historical perspective: phosphatidylserine and phosphatidylethanolamine from the 1800s to the present. Journal of lipid research 59, 923-944 (2018). 2. S. B. Sousa et al., Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome. Nature genetics 46, 70-76 (2014). 3. J. Omi et al., Phosphatidylserine synthesis controls oncogenic B cell receptor signaling in B cell lymphoma. The Journal of cell biology 223, (2024). 4. Y. Yoshihama et al., Potent and Selective PTDSS1 Inhibitors Induce Collateral Lethality in Cancers with PTDSS2 Deletion. Cancer research 82, 4031-4043 (2022). 5. M. N. Trinh et al., Interplay between Asters/GRAMD1s and phosphatidylserine in intermembrane transport of LDL cholesterol. Proceedings of the National Academy of Sciences of the United States of America 119, (2022). 6. M. N. Trinh et al., Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine. Proceedings of the National Academy of Sciences of the United States of America 117, 18521-18529 (2020). 7. T. Long, Y. Sun, A. Hassan, X. Qi, X. Li, Structure of nevanimibe-bound tetrameric human ACAT1. Nature 581, 339-343 (2020). 8. Y. Liu et al., Mechanisms and inhibition of Porcupine-mediated Wnt acylation. Nature 607, 816-822 (2022). https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cell.2024.08.004 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2023-09-06

·BioSpace

Repare Therapeutics to Participate at the Morgan Stanley 21st Annual Global Healthcare Conference

CAMBRIDGE, Mass. & MONTREAL--(BUSINESS WIRE)-- Repare Therapeutics Inc. (“Repare” or the “Company”) (Nasdaq: RPTX), a leading clinical-stage precision oncology company, today announced that members of its senior management team will participate in a fireside chat at the Morgan Stanley 21st Annual Global Healthcare Conference on Wednesday, September 13, 2023, at 11:30 a.m. Eastern Time in New York, NY. A live webcast of the fireside chat can be accessed in the Investor section of the Company’s website at . A replay of the webcast will be archived on the Company’s website for 90 days. About Repare Therapeutics, Inc. Repare Therapeutics is a leading clinical-stage precision oncology company enabled by its proprietary synthetic lethality approach to the discovery and development of novel therapeutics. The Company utilizes its genome-wide, CRISPR-enabled SNIPRx® platform to systematically discover and develop highly targeted cancer therapies focused on genomic instability, including DNA damage repair. The Company’s pipeline includes lunresertib (also known as RP-6306), a PKMYT1 inhibitor currently in Phase 1 clinical development; camonsertib (also known as RP-3500 or RG6526), a potential leading ATR inhibitor currently in Phase 1/2 clinical development and partnered with Roche; RP-3467, a preclinical Polθ inhibitor program; as well as several additional, undisclosed preclinical programs, including RP-1664. For more information, please visit reparerx.com. SNIPRx® is a registered trademark of Repare Therapeutics Inc.

临床1期

2023-09-06

·BioSpace

Aprea Therapeutics to Present at the H.C. Wainwright 25th Annual Global Investment Conference

DOYLESTOWN, Pa., Sept. 06, 2023 (GLOBE NEWSWIRE) -- Aprea Therapeutics, Inc. (Nasdaq: APRE) (“Aprea” or the “Company”), a clinical stage biopharmaceutical company focused on precision oncology through synthetic lethality, today announced that Oren Gilad, Ph.D., President and Chief Executive Officer, will present a corporate overview at the H.C. Wainwright 25th Annual Global Investment Conference, which is scheduled to take place on September 11-13, 2023 in New York, NY. Management will also be available for one-on-one meetings. Details are as follows: H.C. Wainwright 25th Annual Global Investment Conference Date: Monday, September 11, 2023 Time: 4:30 pm ET Location: New York, NY and virtual Registration Link: Click HERE The webcast will also be available for viewing and replay on the “News and Events” tab of the Company’s website ( ). A replay of the webcast will be archived on the Company’s website for 90 days following the presentation. About Aprea Aprea Therapeutics, Inc. is a clinical stage biopharmaceutical company headquartered in Doylestown, Pennsylvania, focused on precision oncology through synthetic lethality. The Company’s lead program is ATRN-119, a clinical-stage small molecule ATR inhibitor being developed for solid tumor indications. Our WEE1 inhibitor is being advanced to IND submission. For more information, please visit the company website at . The Company may use, and intends to use, its investor relations website at as a means of disclosing material nonpublic information and for complying with its disclosure obligations under Regulation FD. Investor Contact: Mike Moyer LifeSci Advisors mmoyer@lifesciadvisors.com

100 项与 Nevanimibe 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11300	-	-	DB16254

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
内源性库欣综合征	临床2期	美国	Millendo Therapeutics US, Inc.	2017-04-13
内源性库欣综合征	临床2期	英国	Millendo Therapeutics US, Inc.	2017-04-13
先天性肾上腺增生	临床2期	美国	Millendo Therapeutics, Inc.	2016-05-18
乙酰辅酶A羧化酶缺乏症	临床1期	美国	Millendo Therapeutics, Inc.	2013-08-13
乙酰辅酶A羧化酶缺乏症	临床1期	德国	Millendo Therapeutics, Inc.	2013-08-13
肾上腺皮质癌	临床1期	美国	Millendo Therapeutics, Inc.	2013-08-13
肾上腺皮质癌	临床1期	德国	Millendo Therapeutics, Inc.	2013-08-13

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03669549 (CTgov)	临床2期	先天性肾上腺增生	15	Nevanimibe HCl (Nevanimibe HCl)	膚廠膚選簾鬱醖淵膚艱(獵膚網積夢繭襯築鑰觸) = 築艱觸鬱夢顧獵積窪構餘鏇鹽遞鏇積獵鬱襯齋 (憲網壓衊鹽鑰艱獵鬱顧, 窪艱艱繭襯糧遞遞鹽簾 ~ 觸糧窪遞簾顧繭遞積糧)	-	2021-03-04
NCT03669549 (CTgov)	临床2期	先天性肾上腺增生	15	Nevanimibe HCl (Nevanimibe HCl Dose Level: <500 mg BID)	範艱齋壓築築衊憲艱壓(網繭積簾衊糧鹹網遞窪) = 簾醖衊顧醖鑰艱選遞獵襯願廠壓鏇淵構遞窪襯 (夢構構窪選醖齋製繭範, 觸鹽網構餘積壓製夢範 ~ 鬱獵壓餘鏇鏇鑰範顧窪) 更多	-	2021-03-04
NCT03053271 (CTgov)	临床2期	内源性库欣综合征	4	ATR-101 (Nevanimibe HCl)	範構選廠餘鏇廠淵顧選(鏇夢膚鏇鏇鏇築鹽鏇鑰) = 廠積衊窪夢淵齋鬱壓鏇鑰網窪鏇襯製遞膚壓襯 (膚製餘窪鹹襯襯築獵構, 網廠範廠鹽鹹衊蓋膚選 ~ 衊膚鬱鑰夢觸鹹範鏇壓) 更多	-	2021-03-02
NCT02804178 (CTgov)	临床2期	先天性肾上腺增生	10	ATR-101	艱膚齋觸衊築壓糧鬱廠(鹹繭淵鹽築齋膚繭願製) = 餘簾夢獵餘齋夢齋顧壓繭鏇鹹選選膚鑰構憲鏇 (築獵選淵窪顧憲觸構築, 鬱窪願憲選鏇積餘蓋選 ~ 醖艱艱醖築艱蓋築齋築) 更多	-	2021-02-17
NCT02804178 (Pubmed \| J Clin Endocrinol Metab) 人工标引	临床2期	先天性肾上腺增生	10	Placebo+Nevanimibe	餘鬱膚糧積積夢衊積範(淵遞製構獵鹹觸鹹襯衊) = 醖夢窪糧構積憲範夢鏇夢簾範襯膚蓋製淵艱憲 (獵鏇襯鑰選鑰蓋鑰衊艱 ) 更多	积极	2020-08-01