(Riviciclib) - 药物靶点：CDK1 x CDK4 x CDK9_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [1]

靶点

CDK1 x CDK4 x CDK9

作用机制

CDK1抑制剂(细胞周期蛋白依赖性激酶1抑制剂)、CDK4抑制剂(细胞周期蛋白依赖性激酶4抑制剂)、CDK9抑制剂(细胞周期蛋白依赖性激酶9抑制剂)

治疗领域

消化系统疾病口颌疾病肿瘤+ [6]

在研适应症-

非在研适应症

晚期胰腺腺癌局部晚期头颈部鳞状细胞癌复发性套细胞淋巴瘤+ [8]

原研机构

Piramal Phytocare Ltd.

在研机构-

非在研机构

Piramal Enterprises Ltd.

Piramal Phytocare Ltd.

最高研发阶段终止临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C21H21Cl2NO5

InChIKeyOOVTUOCTLAERQD-OJMBIDBESA-N

CAS号920113-03-7

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关联

14

项与 Riviciclib 相关的临床试验

NCT01903018 / Completed临床2期

A Multicenter, Phase II/III Study to Assess Radiation Induced Mucositis in Subjects With Locally Advanced Squamous Cell Carcinoma of the Head and Neck Administered Cisplatin and Radiation With or Without P276-00

A Clinical Study to Assess Radiation Induced Mucositis in Subjects with Locally Advanced Squamous Cell Carcinoma of the Head and Neck

开始日期2012-07-01

申办/合作机构

Piramal Enterprises Ltd.

NCT01333137 / Terminated临床1期

An Open-Label Randomized Phase II Trial Comparing Gemcitabine and Carboplatin With and Without P276-00 in Subjects With Metastatic Triple Negative Breast Cancer, With a Phase I Run-in of Escalating Dose of P276-00 Added to Gemcitabine and Carboplatin

P276-00 is a novel, potent, small-molecule, flavone-derived Cdk 4 D1, Cdk1 B, and Cdk9 T inhibitor, with potent cytotoxic effects against chemosensitive and chemoresistant cancer cell lines.This study is planned to compare efficacy of the standard chemotherapy regimen of gemcitabine and carboplatin when administered with or without P276-00 in subjects with advanced triple negative breast cancer.

开始日期2011-08-01

申办/合作机构

Piramal Enterprises Ltd.

NCT00843050 / Terminated临床2期

Single-Arm, Open-Label, Multicenter Phase II Study to Evaluate the Efficacy and Safety of P276-00 in Patients With Relapsed and/or Refractory Mantle Cell Lymphoma

The purpose of this study is to determine whether P276-00 is safe and effective in treatment of Mantle Cell Lymphoma that is recurred after or not responding to at least one previous line of treatment.

开始日期2009-11-01

申办/合作机构

Piramal Enterprises Ltd.

100 项与 Riviciclib 相关的临床结果

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100 项与 Riviciclib 相关的转化医学

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100 项与 Riviciclib 相关的专利（医药）

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29

项与 Riviciclib 相关的文献（医药）

2023-03-01·Expert opinion on therapeutic targets

Molecular pharmacology of multitarget cyclin-dependent kinase inhibitors in human colorectal carcinoma cells.

Article

作者: Manohar, Sonal M. ; Joshi, Kalpana S.

BACKGROUNDColorectal cancer (CRC) is a leading cause of cancer death. Certain signaling pathways are implicated in colorectal carcinogenesis. Cyclin-dependent kinases (CDKs) are commonly hyperactivated in CRC and hence multitarget CDK inhibitors serve as promising therapeutic drugs against CRC.OBJECTIVEOff-target effects of multitarget CDK inhibitors with differential CDK inhibitory spectrum viz. P276-00 (also known as riviciclib), roscovitine and UCN-01 on CRC cell lines of varied genetic background were delineated.METHODProtein expression was analyzed for key signaling proteins by western blotting. β-catenin localization was assessed using immunofluorescence. HIF-1 transcriptional activity and target gene expression were studied by reporter gene assay and RT-PCR respectively. Anti-migratory and anti-angiogenic potential was evaluated by wound healing assay and endothelial tube formation assay.RESULTSCDK inhibitors modulated various signaling pathways in CRC and for certain proteins showed a highly cell line-dependent response. Riviciclib and roscovitine inhibited HIF-1 transcriptional activity and HIF-1α accumulation in hypoxic HCT116 cells. Both of these drugs also abrogated migration of HCT116 and in vitro angiogenesis in HUVECs.CONCLUSIONAnticancer activity of multitarget CDK inhibitors can be certainly attributed to their off-target effects and should be analyzed while assessing their therapeutic utility against CRC.

2023-03-01·Functional & Integrative Genomics

Transcriptome analysis and differential expression in Arabidopsis thaliana in response to rohitukine (a chromone alkaloid) treatment

Article

作者: Gandhi, Sumit G ; Mir, Bilal Ahmad ; Chouhan, Rekha ; Junaid, Alim ; Thakur, Jitendra ; Jamwal, Vijay Lakshmi ; Ahmed, Sajad

Rohitukine is a chromone alkaloid and precursor of potent anticancer drugs flavopiridol, P-276-00, and 2,6-dichloro-styryl derivative (11d) (IIIM-290). The metabolite is reported to possess anticancer, anti-inflammatory, antiadipogenic, immunomodulatory, gastroprotective, anti-implantation, antidyslipidemic, anti-arthritic, and anti-fertility properties. However, the physiological role of rohitukine in plant system is yet to be explored. Here, we studied the effect of rohitukine isolated from Dysoxylum gotadhora on Arabidopsis thaliana. The A. thaliana plants grown on a medium fortified with different rohitukine concentrations showed a significant effect on the growth and development. The root growth of A. thaliana seedlings showed considerable inhibition when grown on medium containing 1.0 mM of rohitukine. Transcriptomic analysis indicated the expression of 895 and 932 genes in control and treated samples respectively at a cut-off of FPKM ≥ 1 and P-value < 0.05. Gene ontology (GO) analysis revealed the upregulation of genes related to photosynthesis, membrane transport, antioxidation, xenobiotic degradation, and some transcription factors (TFs) in response to rohitukine. Conversely, rohitukine downregulated several genes including RNA helicases and those involved in nitrogen compound metabolism. The RNA-seq result was also validated by real-time qRT-PCR analysis. In light of these results, we discuss (i) likely ecological importance of rohitukine in parent plant as well as (ii) comparison between responses to rohitukine treatment in plants and mammals.

2023-02-01·Heliyon

Rohitukine content across the geographical distribution of Dysoxylum binectariferum Hook F. and its natural derivatives as potential sources of CDK inhibitors

Article

作者: Suraj, R Hosur ; Aishwarya, K ; Varun, E ; Bhakti, K ; Jagadish, M R ; Mohana Kumara, P

Dysoxylum binectariferum is an important medicinal plant distributed in the Western Ghats of India. The species has gained international importance for its anticancer component, rohitukine, a chromone alkaloid. Flavopiridol, P-276-00 and IIIM-290 are the derivatives of rohitukine in clinical trials against a wide range of cancers. Flavopiridol was recently approved as an orphan drug for chronic lymphocytic leukemia treatment. In this study, we report the isolation and characterization of rohitukine from the bark of D. binectariferum. Further, rohitukine was estimated across the Western-Ghats and the North-East regions of India. Additionally, D. binectariferum is also reported (∼45 compounds) to produce many natural derivatives of rohitukine and terpenoids, which were investigated in-silico to reveal promising CDK inhibitors. The metabolite fingerprinting of tissues of D. binectariferum was studied using HPTLC and FTIR. The distribution of major chromone alkaloid rohitukine was estimated by HPLC. Further, the pharmacological potential of D. binectariferum compounds was evaluated in-silico by discovering the potential protein targets, molecular docking, ADMET analysis and MD simulation. The isolation of rohitukine has yielded 0.6% from the bark of D. binectariferum. A higher percent of rohitukine was found in the Jog populations (0.58% & 1.28%: leaf & bark), whereas least was observed in the Phasighat population (∼0.06%: both leaf & bark). Across the geographic regions, a higher percent of rohitukine was found in the Central-southern Western Ghats, whereas lower in the northern parts of the Western Ghats and Northeast regions. The leaves produce a considerably higher percent of rohitukine and could be used as a sustainable source of rohitukine. The rohitukine analogues, along with other chromone alkaloids of D. binecatariferum were found to be more interactive with the "kinases" family of proteins, majorly "Serine/threonine-protein kinase PFTAIRE-2" (CDK15) with high confidence level (0.94-0.98). The molecular docking of these chromone alkaloids found a strong binding energy with six CDKs (-3.1 to -10.6 kcal/mol) along with a promising ADMET profile. In addition, molecular dynamic simulation found that the rohitukine complexes are virtually constant with CDK-1, 2, 9 and 15, which is substantiated with MM-PBSA free energy calculations. The chromone alkaloids, majorly rohitukine and its analogues were closely clustered with flavopiridol, P-276-00 and IIIM-290 along with other chrotacumines in the chemical phylogeny. In conclusion, D. binectariferum is a rich source of chromone alkaloids, which could lead to the discovery of more potential scaffolding for CDK inhibitors as anticancer drugs.

100 项与 Riviciclib 相关的药物交易

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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
复发性套细胞淋巴瘤	临床3期	印度	Piramal Enterprises Ltd.	2009-11-01
黑色素瘤	临床3期	印度	Piramal Enterprises Ltd.	2009-05-01
黑色素瘤	临床3期	澳大利亚	Piramal Enterprises Ltd.	2009-05-01
黑色素瘤	临床3期	新西兰	Piramal Enterprises Ltd.	2009-05-01
粘膜炎	临床3期	-	Piramal Phytocare Ltd.	-
复发性套细胞淋巴瘤	临床2期	美国	Piramal Enterprises Ltd.	2009-11-01
难治性套细胞淋巴瘤	临床2期	美国	Piramal Enterprises Ltd.	2009-11-01
晚期胰腺腺癌	临床1期	印度	Piramal Enterprises Ltd.	2009-05-01
浆细胞骨髓瘤难治	临床1期	印度	Piramal Enterprises Ltd.	2008-01-01
复发性多发性骨髓瘤	临床1期	印度	Piramal Enterprises Ltd.	2008-01-01

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临床结果

适应症

分期

评价

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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


NCT00843050 (CTgov)	临床2期	难治性套细胞淋巴瘤	13	P276-00	顧窪膚積觸簾餘憲醖選(齋遞艱鏇夢齋衊鏇築淵) = 襯壓壓繭網襯餘願獵簾夢構蓋築獵選襯築製觸 (憲膚醖壓鹽繭餘選遞簾, 齋廠衊廠遞壓膚鑰鬱艱 ~ 廠築憲選壓網鹹構獵鏇) 更多	-	2012-07-27
AACR2009	临床1期	晚期癌症	47	P276-00	顧鹽齋範顧廠淵夢鑰窪(築膚鬱衊築獵憲醖蓋願) = 衊憲築餘艱膚鬱範蓋遞蓋壓積網醖網觸襯夢窪 (齋鹽艱構獵窪齋壓構獵 ) 更多	-	2009-05-01
ASCO2007	临床1期	晚期癌症	22	P276-00	(鬱築繭獵蓋鑰顧網艱觸) = 衊醖範壓廠製衊觸衊襯夢獵窪膚觸廠艱齋簾選 (鬱淵憲艱築襯鬱憲製鹽 )	-	2007-06-20