Delving into the Latest Updates on S-81694 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [4]

Target

RPS27 x TTK

Action

inhibitors

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 (United States)

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Structure/Sequence

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

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100 Translational Medicine associated with S-81694

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100 Patents (Medical) associated with S-81694

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17

Literatures (Medical) associated with S-81694

24 Oct 2024·The Journal of Physical Chemistry Letters

Prediction of Threonine-Tyrosine Kinase Receptor–Ligand Unbinding Kinetics with Multiscale Milestoning and Metadynamics

Article

Author: Amaro, Rommie E. ; Ojha, Anupam Anand ; Asada, Naoya ; Votapka, Lane W.

Accurately describing protein-ligand binding and unbinding kinetics remains challenging. Computational calculations are difficult and costly, while experimental measurements often lack molecular detail and can be unobtainable. Here, we extend our multiscale milestoning method, Simulation-Enabled Estimation of Kinetics Rates (SEEKR), with metadynamics molecular dynamics simulations to yield accurate small molecule drug residence times. Using the pharmaceutically relevant threonine-tyrosine kinase (TTK) and eight long-residence-time (tens of seconds to hours) inhibitors, we demonstrate accurate prediction of absolute and rank-ordered ligand residence times and free energies of binding.

01 Jul 2022·European Journal of CancerQ1 · 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: Sleijfer, Stefan ; Awada, Ahmad ; Dumez, Herlinde ; Felloussi, Zakia ; 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.

01 May 2022·European Journal of PharmacologyQ3 · MEDICINE

Multiple actions of NMS-P715, the monopolar spindle 1 (MPS1) mitotic checkpoint inhibitor in liver fluke-associated cholangiocarcinoma cells

Q3 · MEDICINE

Article

Author: Wongkham, Sopit ; Waenphimai, Orawan ; Sawanyawisuth, Kanlayanee ; Vaeteewoottacharn, Kulthida ; Mahalapbutr, Panupong

AIMNMS-P715 is a potent inhibitor of monopolar spindle 1 (MPS1) mitotic checkpoint kinase. Overexpression of MPS1 is associated with short survival times in patients with cholangiocarcinoma (CCA). This study investigated the anti-cancer effects of NMS-P715 in human CCA cell lines.MAIN METHODSKKU-100 and KKU-213A CCA cell lines were treated with NMS-P715 and cell viability was determined using MTT and colony formation assays. Inhibitory effects of NMS-P715 on cell cycle and apoptosis were evaluated using flow cytometry. Expression of underlying mechanism-related proteins was examined by Western blotting. Mitotic catastrophe was assessed by counting abnormal nuclei. Transwell assays were used to examine cell migration and invasion.KEY FINDINGSMolecular docking showed that the NMS-P715/MPS1 complex was driven by an induced-fit mechanism. We provide new evidence that NMS-P715 potently inhibited cell proliferation and colony formation in both CCA cell lines. This was accompanied by induction of G2/M arrest and the consequent induction of mitotic catastrophe, a process that occurs during defective mitosis. The recent study showed that NMS-P715 activated caspase-dependent apoptosis and autophagosome formation with an increase of LC3 A/B-II protein expression in CCA cell lines. NMS-P715 also greatly impeded cell migration and invasion in CCA cell lines. The combination of NMS-P715 and gemcitabine or cisplatin showed synergistic effects on CCA cell proliferation.SIGNIFICANCEThis study revealed for the first time that NMS-P715 is a promising candidate for combating CCA owing via multiple actions and may be suitable for further development in a clinical study.

100 Deals associated with S-81694

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Phase 2	-	Nerviano Medical Sciences S.r.l	-
Breast Cancer	Phase 2	-	Les Laboratoires Servier SAS	-
Metastatic breast cancer	Discovery	Belgium	Adir SRL	04 Jan 2018
Metastatic breast cancer	Discovery	Netherlands	Adir SRL	04 Jan 2018
Metastatic breast cancer	Discovery	Belgium	Institut de Recherches Intern Servier	04 Jan 2018
Metastatic breast cancer	Discovery	Netherlands	Institut de Recherches Intern Servier	04 Jan 2018
Metastatic breast cancer	Discovery	France	Adir SRL	04 Jan 2018
Metastatic breast cancer	Discovery	Japan	Institut de Recherches Intern Servier	04 Jan 2018
Metastatic breast cancer	Discovery	France	Institut de Recherches Intern Servier	04 Jan 2018
Metastatic breast cancer	Discovery	Japan	Adir SRL	04 Jan 2018

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


EUCTR2020-001002-26-IT (MPSA-153-001, Corporate Publications) Manual	Phase 1/2	Unresectable Hepatocellular Carcinoma	12	NMS-01940153E (dose-finding)	(qxmpujtxkw) = oiojcrtzxl fxemkecama (egrtolcsee ) View more	Positive	28 Oct 2022
EUCTR2020-001002-26-IT (MPSA-153-001, ENA2022) Manual	Phase 1/2	Unresectable Hepatocellular Carcinoma	-	NMS-153	(vvbjvzhmwv) = zrxxavylya vsozdaszld (jqvsxqkpkm ) View more	Positive	28 Oct 2022
ISRCTN35641359 (2014-002023-10, Pubmed \| Eur J Cancer)	Phase 1	Metastatic Solid Tumor	38	S81694	oxzwxvwazg(fbvipsuaho) = tbxombxfof etzsnaikta (shqxxloent ) View more	-	11 May 2022