Delving into the Latest Updates on S-81694 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

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, NMS 01940153E, NMS P153

+ [5]

Target

RPS27 x TTK

Mechanism

RPS27 inhibitors(ribosomal protein S27 inhibitors), TTK inhibitors(Dual specificity protein kinase TTK inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesDigestive System Disorders

Active Indication

Breast CancerUnresectable Hepatocellular Carcinoma

Inactive Indication

Acute Myeloid LeukemiaMetastatic breast cancerMetastatic Triple-Negative Breast Carcinoma+ [1]

Originator Organization

Nerviano Medical Sciences S.r.l

Active Organization

Nerviano Medical Sciences S.r.l

Les Laboratoires Servier SAS

Inactive Organization

Adir SRLInstitut de Recherches Intern ServierNerviano Medical Sciences Group SRL

Drug Highest PhasePhase 2

First Approval Date-

RegulationOrphan Drug (US)

Login to view timeline

Structure

Molecular FormulaC35H39F3N8O3

InChIKeyJFOAJUGFHDCBJJ-UHFFFAOYSA-N

CAS Registry1202055-32-0

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.

Start Date13 Nov 2020

Sponsor / Collaborator

Nerviano Medical Sciences S.r.l

NCT03411161 / CompletedPhase 1/2IIT

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.

Start Date04 Jan 2018

Sponsor / Collaborator

Institut de Recherches Intern Servier

[+1]

NL-OMON47049 / CompletedNot Applicable

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

Start Date01 Dec 2015

Sponsor / Collaborator-

100 Clinical Results associated with S-81694

Login to view more data

100 Translational Medicine associated with S-81694

Login to view more data

100 Patents (Medical) associated with S-81694

Login to view more data

2

Literatures (Medical) associated with S-81694

01 Jul 2022·European journal of cancer (Oxford, England : 1990)Q1 · MEDICINE

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

Q1 · MEDICINE

Article

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

BACKGROUND:

S81694 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 METHODS:

This 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.

RESULTS:

38 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.

CONCLUSIONS:

S81694 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 REGISTRATION:

EudraCT number: 2014-002023-10; ISRCTN registry ISRCTN35641359.

01 Nov 2005·Journal of medicinal chemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

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

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 Deals associated with S-81694

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Unresectable Hepatocellular Carcinoma	Phase 2	US	Nerviano Medical Sciences S.r.l	13 Nov 2020
Unresectable Hepatocellular Carcinoma	Phase 2	IT	Nerviano Medical Sciences S.r.l	13 Nov 2020
Unresectable Hepatocellular Carcinoma	Phase 2	ES	Nerviano Medical Sciences S.r.l	13 Nov 2020
Metastatic breast cancer	Phase 2	JP	Adir SRL	04 Jan 2018
Metastatic breast cancer	Phase 2	JP	Institut de Recherches Intern Servier	04 Jan 2018
Metastatic breast cancer	Phase 2	BE	Adir SRL	04 Jan 2018
Metastatic breast cancer	Phase 2	BE	Institut de Recherches Intern Servier	04 Jan 2018
Metastatic breast cancer	Phase 2	FR	Adir SRL	04 Jan 2018
Metastatic breast cancer	Phase 2	FR	Institut de Recherches Intern Servier	04 Jan 2018
Metastatic breast cancer	Phase 2	NL	Institut de Recherches Intern Servier	04 Jan 2018

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


EUCTR2020-001002-26-IT (MPSA-153-001, EASL_LCS2023)	Phase 1/2	Unresectable Hepatocellular Carcinoma	-	NMS-01940153E (NMS-153)	cfegvefqxl(dimdwgstyy) = bcacyoevem jsmqybyxxr (znrhhhfulm ) View more	Positive	20 Apr 2023
EUCTR2020-001002-26-IT (MPSA-153-001, Corporate Publications) Manual	Phase 1/2	Unresectable Hepatocellular Carcinoma	12	NMS-01940153E (dose-finding)	qhqwuxynyz(qtywyxjwyy) = tzfbhumiis vserunfieo (yzsapzeigf ) View more	Positive	28 Oct 2022
EUCTR2020-001002-26-IT (MPSA-153-001, ENA2022) Manual	Phase 1/2	Unresectable Hepatocellular Carcinoma	-	NMS-153	hocygujffw(uhfumonsgm) = lufqyjqbit jlngzjwvhh (ouvhqjjiav ) View more	Positive	28 Oct 2022
ISRCTN35641359 (2014-002023-10, Pubmed \| Eur J Cancer)	Phase 1	Metastatic Solid Tumor	38	S81694	(cofogjxmmq) = yhiwrompje xrozfcldic (rbpnfufkjx ) View more	-	11 May 2022