S-81694(S-81694) - 药物靶点：RPS27 x TTK_在研适应症：乳腺癌，不可切除的肝细胞癌_专利_临床

概要

基本信息

药物类型

小分子化药

别名

N-(2,6-diethyphenyl)-8-({4-[4-(dimethylamino)piperidin-1-yl]-2- methoxyphenyl}amino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide phosphate

+ [5]

靶点

RPS27 x TTK

作用机制

RPS27 inhibitors(ribosomal protein S27 inhibitors)、TTK抑制剂(TTK蛋白激酶抑制剂)

治疗领域

肿瘤皮肤和肌肉骨骼疾病消化系统疾病

在研适应症

乳腺癌不可切除的肝细胞癌

非在研适应症

急性髓性白血病转移性乳腺癌转移性三阴性乳腺癌+ [1]

原研机构

Nerviano Medical Sciences S.r.l

在研机构

Nerviano Medical Sciences S.r.l

Les Laboratoires Servier SAS

非在研机构

Adir SRLInstitut de Recherches Intern ServierNerviano Medical Sciences Group SRL

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (美国)

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结构

分子式C35H39F3N8O3

InChIKeyJFOAJUGFHDCBJJ-UHFFFAOYSA-N

CAS号1202055-32-0

关联

4

项与 S-81694 相关的临床试验

NCT05630937 / Completed临床1/2期

Phase I/II Study on Safety and Efficacy of NMS-01940153E in Adult Patients With Unresectable Hepatocellular Carcinoma (HCC) Previously Treated With Systemic Therapy

This is a Phase I/II, open-label, non-randomized, multicenter study to explore safety, tolerability and antitumor activity of NMS-01940153E as single agent in adult patients with unresectable hepatocellular carcinoma (HCC) previously treated with systemic therapy.
The Phase I portion is designed as a dose-escalation study in sequential cohorts of patients aimed to obtain the maximum tolerated dose (MTD) that is defined based on the dose limiting toxicities (DLTs) observed in the first cycle of treatment.
The Phase II portion is designed as a two-stage study with an interim analysis for futility and stopping criteria for unacceptable toxicity to assess the antitumor activity of NMS-01940153E in adult patients with unresectable HCC previously treated with systemic therapy measured as objective response rate.

开始日期2020-11-13

申办/合作机构

Nerviano Medical Sciences S.r.l

NCT03411161 / Completed临床1/2期IIT

Phase I/II Trial of S 81694 Administered Intravenously in Combination With Paclitaxel to Evaluate the Safety, Pharmacokinetic and Efficacy in Metastatic Breast Cancer

The purpose of this study is to determine the safety profile, the maximum tolerated dose (MTD) and the associated dose-limiting toxicities (DLTs) of S 81694 in combination with paclitaxel in metastatic breast cancer (mBC) patients, and to investigate the antitumour activity of the combination in metastatic triple negative breast cancer (mTNBC) patients.

开始日期2018-01-04

申办/合作机构

Institut de Recherches Intern Servier

[+1]

NL-OMON47049 / CompletedN/AIIT

Phase I dose-escalation study of S 81694 administered intravenously in adult patients with advanced/metastatic solid tumours - CL1-81694-001: study of S 81694 in patients with solid tumors

开始日期2015-12-01

申办/合作机构-

100 项与 S-81694 相关的临床结果

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100 项与 S-81694 相关的转化医学

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100 项与 S-81694 相关的专利（医药）

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2

项与 S-81694 相关的文献（医药）

2022-07-01·European Journal of Cancer1区 · 医学

First-in-man, first-in-class phase I study with the monopolar spindle 1 kinase inhibitor S81694 administered intravenously in adult patients with advanced, metastatic solid tumours

1区 · 医学

Article

作者: Sleijfer, Stefan ; Awada, Ahmad ; Felloussi, Zakia ; Dumez, Herlinde ; de Jonge, Maja ; de la Bigne, Anne-Marie ; Cantero, Frederique ; Ammattatelli, Katia ; Schöffski, Patrick ; Burbridge, Mike ; Maruzzelli, Sara ; Colombo, Riccardo ; Aftimos, Philippe

BACKGROUNDS81694 is an inhibitor of monopolar spindle 1 kinase, a target expressed in proliferating cells. CL1-81694-001 was the first-in-human study aiming at identifying a safe dosing schedule in solid tumour patients.PATIENTS AND METHODSThis trial was based on inter-individual dose-escalation of single agent S81694 in cohorts of ≥3 patients to assess the safety and tolerability and determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose (RP2D), with S81694 given on days 1,8,15 of a 28-day cycle as 1-h infusion.RESULTS38 patients were treated at doses ranging from 4 to 135 mg/m²/week; 144 cycles were administered (median 2/patient; range 1-32 cycles). Patients discontinued treatment for disease progression (78.9%), adverse events (AE; 18.4%) or withdrawal of consent (2.6%). Treatment modifications occurred in 22 patients (57.9%; 49 cycles). Common treatment-emergent AEs were fatigue (22 patients;57.9%), anaemia (17;44.7%) and nausea (12;31.6%). Haematological toxicity was mild, with Grade 3 anaemia observed in three patients and neutropenia mainly seen at the 135 mg/m² dose level. Three first cycle DLTs included G3 anaemia (4 mg/m² dose), G4 hypertension (20 mg/m²), G3 fatigue (135 mg/m²). MTD was not reached due to premature discontinuation of enrolment based on a sponsor decision. Among 35 patients evaluable for response, one (renal cell carcinoma) had a complete response, one (hepatocellular carcinoma) had a transient decrease of target lesions and 13 had stable disease. Seven patients remained on study for ≥6 cycles, two at the 135 mg/m² dose.CONCLUSIONSS81694 can be administered safely as a single agent in adults with solid tumours on days 1,8,15 of a 28-day cycle up to a dose of 135 mg/m²/week without reaching MTD. The RP2D was not defined due to the prioritization of the use of S81694 in combination with cytotoxic agents, based on emerging preclinical data.TRIAL REGISTRATIONEudraCT number: 2014-002023-10; ISRCTN registry ISRCTN35641359.

2005-11-01·Journal of Medicinal Chemistry1区 · 医学

Tricyclic Pyrazoles. 3. Synthesis, Biological Evaluation, and Molecular Modeling of Analogues of the Cannabinoid Antagonist 8-Chloro-1-(2‘,4‘-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6- tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide

1区 · 医学

Article

作者: Murineddu, Gabriele ; Pani, Luca ; Reali, Roberta ; Loriga, Giovanni ; Ruiu, Stefania ; Manca, Ilaria ; Pinna, Gérard A. ; Toma, Lucio ; Lazzari, Paolo

A series of analogues of 8-chloro-1-(2',4'-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide 4a (NESS 0327) (Ruiu, S.; Pinna, G. A.; Marchese, G.; Mussinu, J. M.; Saba, P.; Tambaro, S.; Casti, P.; Vargiu, R.; Pani, L. Synthesis and Characterization of NESS 0327: A Novel Putative Antagonist of CB1 Cannabinoid Receptor. J. Pharmacol. Exp. Ther. 2003, 306, 363-370) was synthesized and evaluated for their affinity to cannabinoid receptors. Depending on the chemical modification of the lead structure that was chosen, compounds 4b, 4c, 4i, 4l, and 4m still proved to be potent binders of the CB1 receptor. Moreover, several analogues (4c, 4d, 4e, and 4m) demonstrated superior CB2 receptor binding affinities compared to the parent ligand. Compounds 4b, 4c, 4i, and 4l displayed the most promising pharmacological profiles, having the highest selectivity for CB1 receptors with Ki(CB2) to Ki(CB1) ratios of 11,250, 2000, 3330 and 4625, respectively. Compound 4c increased the intestinal propulsion in mice and antagonized the effect induced by the CB1 receptor agonist WIN 55,212-2. Finally, molecular modeling studies were carried out on a set of tricyclic pyrazoles (2a-4a) and on rimonabant 1 (SR141716A), indicating that high CB1 receptors affinities were consistent for the tricyclic derivatives, both with a nonplanar geometry of the tricyclic cores and with a precise orientation of the substituent (chlorine) on this ring system.

100 项与 S-81694 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
乳腺癌	临床2期	-	Nerviano Medical Sciences S.r.l	-
乳腺癌	临床2期	-	Les Laboratoires Servier SAS	-
转移性三阴性乳腺癌	临床1期	法国	Adir SRL	2018-01-04
转移性三阴性乳腺癌	临床1期	荷兰	Adir SRL	2018-01-04
转移性三阴性乳腺癌	临床1期	日本	Institut de Recherches Intern Servier	2018-01-04
转移性三阴性乳腺癌	临床1期	比利时	Adir SRL	2018-01-04
转移性三阴性乳腺癌	临床1期	日本	Adir SRL	2018-01-04
转移性三阴性乳腺癌	临床1期	法国	Institut de Recherches Intern Servier	2018-01-04
转移性三阴性乳腺癌	临床1期	荷兰	Institut de Recherches Intern Servier	2018-01-04
转移性三阴性乳腺癌	临床1期	比利时	Institut de Recherches Intern Servier	2018-01-04

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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


EUCTR2020-001002-26-IT (MPSA-153-001, Corporate Publications) 人工标引	临床1/2期	不可切除的肝细胞癌	12	NMS-01940153E (dose-finding)	(鏇糧繭壓範淵鹹壓顧糧) = 淵網簾齋簾糧鹽衊鹹窪顧簾繭蓋鏇積糧糧淵觸 (範鑰糧蓋鬱鹹鏇糧獵齋 ) 更多	积极	2022-10-28
EUCTR2020-001002-26-IT (MPSA-153-001, ENA2022) 人工标引	N/A	不可切除的肝细胞癌	-	NMS-153	(積憲願餘鬱蓋糧觸窪醖) = 蓋遞艱蓋積淵觸鏇範繭獵糧壓蓋積淵製艱餘窪 (憲願鏇遞襯夢廠鬱選願 ) 更多	积极	2022-10-28
ISRCTN35641359 (2014-002023-10, Pubmed \| Eur J Cancer)	临床1期	转移性实体瘤	38	S81694	(鏇鹽齋願繭壓選膚蓋齋) = 艱獵願醖窪觸顧鬱鹽網夢願積廠廠願鏇餘膚鹹 (製膚壓遞網艱鹽窪壓觸 ) 更多	-	2022-05-11