Evaluate the effect of the addition of inecalcitol to decitabine treatment on overall survival in previously untreated AML patients aged 65 years or more who are randomly assigned to receive decitabine with or without inecalcitol.

开始日期2016-06-01

申办/合作机构

Aton SA

NCT02949570

/ Unknown status临床2期

Phase 2 Study to Assess Efficacy and Safety of Inecalcitol in Imatinib-Treated Residual Chronic Myeloid Leukaemia: INIM Study

To assess the efficacy of inecalcitol in combination with imatinib in CML patients with molecular residual disease on imatinib monotherapy.

开始日期2014-02-01

申办/合作机构

Aton SA

100 项与伊奈骨化醇相关的临床结果

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100 项与伊奈骨化醇相关的转化医学

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100 项与伊奈骨化醇相关的专利（医药）

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项与伊奈骨化醇相关的文献（医药）

2024-12-01·ANTICANCER RESEARCH

Synergistic Effects of Inecalcitol With Imatinib and Dasatinib on Chronic Myeloid Leukemia Cell Lines

Article

作者: Angel, Samuel ; Venkatachalam, Kallidaikurichi V ; Cowles, Emma ; Ani, Raad Al ; Costa, Jeams

BACKGROUND/AIM:

According to American Cancer Society's recent estimates, about 5,330 men and 3,950 women are diagnosed each year with chronic myeloid leukemia (CML). Roughly, 750 men and 530 women are predicted to die as a result of CML, establishing a dire need for advancements in CML treatment. Tyrosine kinase inhibitors (TKIs) imatinib and dasatinib have profound effects for prognosis and delaying survival from CML. The role of inecalcitol in the treatment and prevention of various cancers including leukemia has been established. The aim of this study was to analyze the putative synergistic treatment effects of inecalcitol in combination with imatinib or dasatinib on various cell lines including AR-230, LAMA-84-s, KCL-22, and U-937.

MATERIALS AND METHODS:

Cells grown in plates were treated alone or with varying combinations of inecalcitol, imatinib, and dasatinib and incubated for 48 h at 37°C. Cell death was determined using MTT assay.

RESULTS:

KCL-22 and U-937 were resistant to both combination treatments, whereas AR-230 exhibited a maximal antiproliferative effect (24%) with the combined treatment of imatinib (0.325 μM) and inecalcitol (15.8 μM) (p<0.001). With dasatinib (0.456 nM) and inecalcitol (15.8 μM), AR-230 exhibited a 34% antiproliferative effect (p<0.001). In drastic contrast, LAMA84-s exhibited a 45% antiproliferative effect (with the combined treatment of imatinib (0.325 μM) and inecalcitol (15.8 μM) (p<0.006). Notably, with dasatinib (0.456 nM) and inecalcitol (15.8 μM), LAMA84-s exhibited approximately 78% cell killing (p<0.007).

CONCLUSION:

The study suggests that the synergistic effects of inecalcitol with imatinib on cell killing are more drastic in some cells than others. These varying effects may be due to differences in cell metabolism.

2024-02-01·Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society

Biological evaluation of combinations of tyrosine kinase inhibitors with Inecalcitol as novel treatments for human chronic myeloid leukemia

Article

作者: Saleh, Maysaa M ; Abuarqoub, Duaa A ; Alyoussef Alkrad, Jamal ; Al-Ali, Luma ; Al-Ani, Raad J ; Najdawi, Manal M ; Naser, Abdallah Y ; Hammad, Alaa M ; Abbas, Manal M ; Abu-Irmaileh, Bashaer

Background:

The use of tyrosine kinase inhibitors (TKIs) as a treatment for chronic myeloid leukemia (CML) has improved the natural history of the disease and increased the duration of survival. Tyrosine kinase inhibitors represent the success of target therapies that work on molecular targets, although some patients still have therapy failure. Vitamin D has antiproliferative, pro-apoptotic, and anti-angiogenic effects on cells, therefore it can be considered as a potential cancer preventative and treatment agent. Inecalcitol (TX-522) is the 14-epi-analogue of Calcitriol (1,25(OH)₂-vitamin D3), and inhibits cancer cell proliferation more effectively than Calcitriol. This study was conducted to evaluate the antiproliferative and synergistic effects of the anticancer drugs Imatinib and Dasatinib in combinations with Inecalcitol on human chronic myeloid leukemia K-562 cells.

Method:

The growth inhibitory activities of Inecalcitol, Imatinib, Dasatinib, and different combinations of one of the two drugs (Imatinib and Dasatinib) with Inecalcitol, were determined in vitro using MTT assay against K-562 cell line.

Results:

Inecalcitol, Imatinib, and Dasatinib showed potent antiproliferative activities against K-562 cells with GI₅₀ values of 5.6 µM, 0.327 µM, and 0.446 nM, respectively. Combinations of Imatinib or Dasatinib with different concentrations of Inecalcitol increased significantly the antiproliferative activities and potencies of both drugs (****p < 0.0001), with optimal GI₅₀ values of 580 pM (Imatinib) and 0.51 pM (Dasatinib). Furthermore, the combination treatments showed synergistic interaction between the antileukemic drugs and Inecalcitol, with combination indices (CI) < 1.

Conclusion:

The study demonstrated that the human chronic myeloid leukemia K-562 cells were subjected to a synergistic growth inhibitory impact when antileukemic drugs (Imatinib or Dasatinib) were combined with Inecalcitol, therefore, it is recommended that these combinations be viewed as promising novel antileukemic medications and used in place of individual medications with lower dosages and negligible side effects in the treatment of CML.

2024-01-01·Natural Product Communications

The Computational Interaction Analyses of Some Vitamin D-Related Compounds with Sterol 14-Demethylase (CYP51) – Could It Be a Glimmer of Hope to Find New Anti-Mucormycotic Drugs Extracted from Plants-Derived Sterols?

作者: Althaiban, Abdullah K. ; Alsubhi, Wael A. ; Faris Shalayel, Mohammed Helmy ; Almutairi, Majed Meshal ; Al-Mazaideh, Ghassab M.

Introduction:

Many vitamin D analogs and sterols-related compounds have been identified and extracted from several plants including Solanaceae species. The aim of our study was to evaluate the antifungal potential of 15 vitamin D, D3 analogs, and some sterols-related compounds that have been detected in some plants along with 3 standard antifungal drugs, Isavuconazole, Fluconazole, and Voriconazole, on the Mucormycosis-sterol 14-alpha demethylase (CYP51) enzyme by in silico study.

Methods:

In this work, the molecular simulation was used to prepare the specific enzyme and the antifungal profiles utilized for the molecular docking of the contemplated compounds and subsequent prediction for the mechanism of binding within the catalytic site of Sterol 14-Demethylase (CYP51) to speculate their binding affinities. Anti-fungal medications, Fluconazole and Voriconazole revealed drugs bound distant from the binding sites, but Isavuconazole bound close to the binding site. In this context, the 15 vitamin D and D3 compounds were somewhat seen in binding proximity, especially for Alfacalcidol, Eldecalcitol, and Inecalcitol.

Results:

Seocalcitol and Isavuconazole had the lowest binding energies and were the closest ones connected to the binding cavities with the best binding free energies equal −13.21 ± 0.24 and −15.29 ± 0.25, respectively.

Conclusion:

Isavuconazole and Seocalcitol could potentially be further assessed to be adjuvantly used as drugs to inhibit the fungal activity by targeting CYP51, a significant target for anti-fungal as well as anti-protozoan drugs, and hence could be efficient against mucormycosis.

项与伊奈骨化醇相关的新闻（医药）

2025-04-02

·化学经纬

1α，25-二羟基维生素D3的化学合成

天然维生素D类化合物是通过动物体或人体内的一些甾醇分子经脱氢和B环开裂转化而来的，如人体皮肤中含有的7-脱氢胆甾醇通过阳光中短紫外线的作用，发生周环反应，7-脱氢胆甾醇分子中的环己二烯开环转变成开链共轭三烯结构（即原维生素D3），第二步，在热的作用下，原维生素D3 中相应的角甲基上一个σ-H 发生[1，7]迁移反应得维生素D3 ，无活性的维生素D3 前体分子经肝脏转化为体内的主要循环形式25-羟基维生素D3，再经过肾脏转化为1α，25-二羟基维生素D31，通过这一活性形式调节各种生理功能。活性维生素D3 主要是1α，25-二羟基维生素D3，除了经典的体内钙磷调节功能外，近年来还发现它具有促进细胞分化和抑制细胞增殖的功能，可用于治疗恶性肿瘤如白血病、乳腺癌、子宫颈癌，皮肤增生性疾患如银屑病、脂溢性皮炎和免疫系统疾病（如AIDS病等）。人们在合成维生素D活性代谢产物如1α，25-二羟基维生素D3 的同时，大量的类似物被合成。在这些合成的类似物中，有的表现出更强的生理活性，如氟代的1α，25-二羟基维生素D3，其活性强度为原有母体分子的5～10倍，分子中含有环氧基团和过氧键侧链的化合物具有抑制骨髓白细胞增生的作用。1α，25-二羟基维生素D3 在治疗剂量时，其钙活性可引起高钙症，使其应用受到限制。1990年Deluca等人发现，当1中A 环19-亚甲基用两个氢取代时，形成的19-失碳-1α，25-二羟基维生素D33，其细胞分化活性明显增加，而钙活性仅是1的十分之一，这一良好结果引起人们对1及其类似化合物合成的极大兴趣。维生素D的一般合成策略是：首先合成由其分子中C5-C6键，或C6-C7键，或C7-C8键断裂形成的A 环和带侧链的CD环，然后通过会聚合成连接A 环和CD环。（1）Wittig-Horner法1975年Lythgoe等通过此方法，完成了维生素D的模型试验，反应中A 环连接的双键未发生迁移，新产生的C7-C8双键构型符合要求。此法成功地应用于1α，25-二羟基维生素D3 的合成。（2）Cross-Coupling法此法是利用金属试剂的偶联反应以C7-C8键连接方式构成维生素D 类化合物，最早由Mourino和Okamula提出。它是通过A 环炔烃与CD环烯三氟甲基磺酸酯的钯催化偶联反应制备。其中A 环炔烃和CD环烯三氟甲基磺酸酯分别由（S）-香芹酮（S-carvone）和格伦德曼（Grundmann）酮为起始原料，格伦德曼酮通常由维生素D3 或维生素D2 臭氧化降解产物二醇6制得。其合成路线如下：（3）通过C6-C7键连接A 环和CD环的合成策略通过C6-C7键连接A 环和CD环的合成策略如下：Vandewalle小组以环丙烷醛衍生物作为A 环合成子，以烯溴衍生物作为CD环合成子，完成了临床试验治疗银屑病药物TX522的合成。在Sato提出的维生素D3 合成方法中，最终两个分子片段的链接就是利用溴代烯烃化合物与硼酸酯化合物的Suzuki偶联反应来完成的。（4）烯炔的钯催化环化反应法———Trost法Tros发展了一个利用烯炔的钯催化环化反应合成维生素D3 的方法，其特点是通过CD环与烯炔反应，同时连接C6-C7键和C10-C15键从而实现1α，25-二羟基维生素D3 的合成。其合成路线如下。Yoshitomo等用Torst策略合成了各种2α-取代的1α，25-二羟基维生素D3类似物。自从1922年麦克勒姆（McCllum）发现维生素D，1927年温道斯（Windaus）推导出麦角甾醇是食物中维生素D的前体以后，早期人们仅仅将其视为一种维生素类物质，后来生物学表明：维生素D也是一种内源性激素物质。以往人们仅仅把维生素D 作为钙和磷的调节剂，用其治疗小儿佝偻病、软骨病和骨质疏松症。1971 年德卢卡（Deluca）、诺曼（Norman）和科迪塞克（Kodicek）三个小组几乎同时确认维生素D最终活性形式为1α，25-二羟基维生素D3。随后的研究表明，活性维生素D类化合物具有细胞诱导分化作用和阻止肿瘤细胞增生作用，可用于治疗肿瘤、银屑病和自身免疫疾病等。活性维生素D 类化合物的化学和生物学研究引起人们高度重视。有机化学家通过各种方法合成了1α，25-二羟基维生素D3 及其大量类似物。对活性维生素D3 的合成至今仍以传统的液相反应为主。由于活性维生素D3 的合成往往要经历很长的反应路线、多步操作及纯化等，目前，合成化学家们利用固相合成的高转化率、简单的洗涤式纯化过程等特点，开发出了用固相方式合成活性维生素D3 的方法。如维生素D3 衍生物骨化三醇（calcitriol）的合成，可对A、C及D环进行完全方式的固相组装，而且A 环增加了结构多样性修饰。近年来由于不对称合成的发展，使用新反应和新试剂提高立体选择性和专一性，人们的注意力更多地转移到汇聚合成的方法上。参考文献[1]Zhu G D，Okamura W H.Chem Rev， 1995，95：1877.[2]Trost B M，Dumas J，Villa M.J Am Chem Soc，1992，114： 9836.[3]Wu Y，Zhao Y，Tian H，et al.Eur J Org Chem，2001，3779.

临床结果临床失败

100 项与伊奈骨化醇相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB04796

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
急性髓性白血病	临床2期	美国	Aton SA	2016-06-01
急性髓性白血病	临床2期	法国	Aton SA	2016-06-01
慢性期慢性髓性白血病	临床2期	法国	Aton SA	2014-02-01
慢性淋巴细胞白血病	临床2期	法国	Aton SA	-
慢性淋巴细胞白血病	临床2期	-	Merck Serono SA	-
费城染色体阳性慢性粒细胞白血病	临床2期	-	Merck Serono SA	-
前列腺癌	临床2期	法国	Aton SA	-
前列腺癌	临床2期	-	Merck Serono SA	-
银屑病	临床2期	美国	-	-
银屑病	临床2期	欧洲	-	-

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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


ASCO2011	临床2期	去势抵抗性前列腺癌	54	Inecalcitol	膚蓋範鹽築選鹽廠窪積(鏇鏇觸願襯齋鏇鏇觸構) = 鹹襯築製繭襯構窪艱繭選積餘遞鏇廠獵鏇網鏇 (範鑰獵鏇觸鬱襯膚壓糧 )	-	2011-05-20
710 (AUA2011)	临床2期	去势抵抗性前列腺癌	54	Inecalcitol	鹹襯膚鹹衊遞衊鏇積選(壓醖衊觸艱範觸壓製獵) = 鑰鏇遞鑰繭襯觸簾衊範襯範願憲鬱範鬱蓋獵膚 (蓋鏇淵願鑰餘願製窪餘 ) 更多	积极	2011-04-01
ASCO_GU2011	临床2期	去势抵抗性前列腺癌	54	Inecalcitol	鑰鏇齋淵鏇膚艱夢築鑰(糧鹹遞憲選鏇糧衊窪獵) = 簾願顧範鏇簾鑰積衊製艱廠憲醖願範繭窪夢鬱 (願積製願鏇獵夢積夢衊 ) 更多	-	2011-03-01