Home Cytoskeletal Signaling Kinesin Inhibitor Ispinesib (SB-715992)

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Ispinesib (SB-715992) Kinesin Inhibitor

Kat.-Nr.: S1452

Ispinesib (SB-715992, CK0238273) ist ein potenter, spezifischer und reversibler Inhibitor des kinesin spindle protein (KSP) mit einem Ki app von 1,7 nM in einem zellfreien Assay, der keine Hemmung von CENP-E, RabK6, MCAK, MKLP1, KHC oder Kif1A zeigt. Diese Verbindung induziert einen mitotischen Arrest und apoptotischen Zelltod.
Ispinesib (SB-715992) Kinesin Inhibitor Chemical Structure

Chemische Struktur

Molekulargewicht: 517.06

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Qualitätskontrolle (Quality Control)

Charge: Reinheit: 99.97%
99.97

Zellkultur, Behandlung & Arbeitskonzentration
(Cell Culture, Treatment & Working Concentration)

Zelllinien Assay-Typ Konzentration Inkubationszeit Formulierung Aktivitätsbeschreibung PMID
HCT116 Antiproliferative assay 72 hrs Antiproliferative activity against human HCT116 cells after 72 hrs by Alamar blue assay, GI50=0.025μM 22248262
hTERT-HME1 Antiproliferative assay 72 hrs Antiproliferative activity against human hTERT-HME1 cells after 72 hrs by Alamar blue assay, GI50=0.032μM 22248262
K562 Antiproliferative assay 72 hrs Antiproliferative activity against human K562 cells after 72 hrs by Alamar blue assay, GI50=0.071μM 22248262
BxPC3 Antiproliferative assay 72 hrs Antiproliferative activity against human BxPC3 cells after 72 hrs by Alamar blue assay, GI50=0.08μM 22248262
NCI-H1299 Antiproliferative assay 72 hrs Antiproliferative activity against human NCI-H1299 cells after 72 hrs by Alamar blue assay, GI50=0.082μM 22248262
LNCAP Growth inhibition assay 72 hrs Growth inhibition of human LNCAP cells after 72 hrs by Alamar blue assay, GI50=0.022μM 23394180
HCT116 Growth inhibition assay 72 hrs Growth inhibition of human HCT116 cells after 72 hrs by Alamar blue assay, GI50=0.025μM 23394180
PC3 Growth inhibition assay 72 hrs Growth inhibition of human PC3 cells after 72 hrs by Alamar blue assay, GI50=0.05μM 23394180
BxPC3 Growth inhibition assay 72 hrs Growth inhibition of human BxPC3 cells after 72 hrs by Alamar blue assay, GI50=0.08μM 23394180
NCI-H1299 Growth inhibition assay 72 hrs Growth inhibition of human NCI-H1299 cells after 72 hrs by Alamar blue assay, GI50=0.082μM 23394180
LXFS 538 Antitumor assay 6 mg/kg Antitumor activity against human LXFS 538 cells xenografted in NMRI nu/nu mouse assessed as tumor regression at 6 mg/kg, ip measured on day 13 23394180
HeLa Antiproliferative assay 48 hrs Antiproliferative activity against human HeLa cells after 48 hrs by MTT assay, IC50=1μM 24184776
MCF7 Antiproliferative assay 48 hrs Antiproliferative activity against human MCF7 cells after 48 hrs by MTT assay, IC50=1.3μM 24184776
HCT116 Growth inhibition assay 72 hrs Growth inhibition of human HCT116 cells after 72 hrs by MTS assay, IC50=0.0011μM 26396688
TC32 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells 29435139
DAOY qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells 29435139
SJ-GBM2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells 29435139
A673 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells 29435139
SK-N-MC qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells 29435139
NB-EBc1 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells 29435139
Saos-2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells 29435139
LAN-5 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells 29435139
BT-12 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells 29435139
OHS-50 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells 29435139
A673 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for A673 cells) 29435139
SK-N-MC qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-MC cells 29435139
BT-12 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-12 cells 29435139
DAOY qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for DAOY cells 29435139
BT-37 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-37 cells 29435139
TC32 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for TC32 cells 29435139
MG 63 (6-TG R) qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for MG 63 (6-TG R) cells 29435139
U-2 OS qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for U-2 OS cells 29435139
Rh41 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh41 cells 29435139
RD qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for RD cells 29435139
Rh30 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh30 cells 29435139
Saos-2 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Saos-2 cells 29435139
SK-N-SH qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-SH cells 29435139
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Chemische Informationen, Lagerung & Stabilität (Chemical Information, Storage & Stability)

Molekulargewicht 517.06 Formel

C30H33ClN4O2

 Lagerung (Ab Erhaltdatum)
CAS-Nr. 336113-53-2 SDF herunterladen Lagerung von Stammlösungen

Synonyme CK0238273 Smiles CC1=CC=C(C=C1)C(=O)N(CCCN)C(C2=NC3=C(C=CC(=C3)Cl)C(=O)N2CC4=CC=CC=C4)C(C)C

Löslichkeit (Solubility)

In vitro
Charge:

DMSO : 103 mg/mL (199.2 mM)
(Feuchtigkeitskontaminiertes DMSO kann die Löslichkeit verringern. Verwenden Sie frisches, wasserfreies DMSO.)

Ethanol : 103 mg/mL

Water : Insoluble

Molaritätsrechner

Masse Konzentration Volumen Molekulargewicht
Verdünnungsrechner Molekulargewicht-Rechner

In vivo
Charge:

In-vivo-Formulierungsrechner (Klare Lösung)

Schritt 1: Geben Sie unten die Informationen ein (Empfohlen: Ein zusätzliches Tier einplanen, um Verluste während des Experiments auszugleichen)

mg/kg g μL

Schritt 2: Geben Sie die In-vivo-Formulierung ein (Dies ist nur der Rechner, nicht die Formulierung. Bitte kontaktieren Sie uns zuerst, wenn im Abschnitt Löslichkeit keine In-vivo-Formulierung angegeben ist.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Berechnungsergebnisse:

Arbeitskonzentration: mg/ml;

Methode zur Herstellung der DMSO-Stammflüssigkeit: mg Wirkstoff voraufgelöst in μL DMSO ( Konzentration der Stammflüssigkeit mg/mL, Bitte kontaktieren Sie uns zuerst, wenn die Konzentration die DMSO-Löslichkeit der jeweiligen Wirkstoffcharge überschreitet. )

Methode zur Herstellung der In-vivo-Formulierung: Nehmen Sie μL DMSO Stammflüssigkeit, fügen Sie als Nächstes hinzuμL PEG300, mischen und aufklären, fügen Sie als Nächstes hinzuμL Tween 80, mischen und aufklären, fügen Sie als Nächstes hinzu μL ddH2O, mischen und aufklären.

Methode zur Herstellung der In-vivo-Formulierung: Nehmen Sie μL DMSO Stammflüssigkeit, fügen Sie als Nächstes hinzu μL Maisöl, mischen und aufklären.

Hinweis: 1. Bitte stellen Sie sicher, dass die Flüssigkeit klar ist, bevor Sie das nächste Lösungsmittel hinzufügen.
2. Achten Sie darauf, die Lösungsmittel in der richtigen Reihenfolge hinzuzufügen. Sie müssen sicherstellen, dass die im vorherigen Schritt erhaltene Lösung klar ist, bevor Sie das nächste Lösungsmittel hinzufügen. Physikalische Methoden wie Vortexen, Ultraschall oder ein warmes Wasserbad können zur Unterstützung des Lösungsvorgangs verwendet werden.

Wirkungsmechanismus (Mechanism of Action)

Eigenschaften
An allosteric, potent, specific, and reversible inhibitor of the mitotic kinesin spindle protein (KSP) (HsEg5).
Targets/IC50/Ki
KSP (HsEg5)
(Cell-free assay)
1.7 nM(Ki app)
In vitro

Ispinesib (SB-715992) is a potent, allosteric, reversible, and specific inhibitor of KSP, which changes the binding property of KSP to microtubules and disturbs its movement by inhibiting ADP release without altering the release of the KSP-ADP complex from the microtubule. This compound shows potent cytotoxic activity in a panel of tumor cell lines, including Colo205, Colo201, HT-29, M5076, Madison-109, and MX-1, with IC50 of 1.2 nM to 9.5 nM. In PC-3 prostate cancer cells, it (15 nM and 30 nM) blocks cell proliferation and induces apoptosis by regulating the expression levels of genes that controls apoptosis, cell proliferation, cell cycle, and cell signaling, such as EGFR, p27, p15, and IL-11. In a panel of 53 breast cell lines, Ispinesib (7.4 nM–600 nM) demonstrates broad inhibitory activity. In BT-474 and MDA-MB-468 cells, it (150 nM) induces apoptosis, as revealed by a higher proportion of apoptotic cells, lower antiapoptotic Bcl-XL level, and higher proapoptotic Bax and Bid levels.

Kinase-Assay
Kinetische Analyse der ATPase-Aktivität von humanem KSP im Steady-State und Hemmung durch Ispinesib
Die Kinesin-Spezifitätsanalyse wird unter Verwendung eines Pyruvatkinase-Laktatdehydrogenase-Nachweissystems durchgeführt, das die Produktion von ADP mit der Oxidation von NADH koppelt. Änderungen der Absorption werden bei 340 nm überwacht. Steady-State-Studien mit nanomolaren Konzentrationen von KSP werden unter Verwendung eines empfindlichen fluoreszenzbasierten Assays durchgeführt, der ein Pyruvatkinase-, Pyruvatoxidase- und Meerrettichperoxidase (HRP)-gekoppeltes Nachweissystem nutzt, das die Generierung von ADP mit der Oxidation von Amplex Red zu fluoreszierendem Resorufin koppelt. Die Generierung von Resorufin wird durch Fluoreszenz überwacht (λAnregung = 520 nm und λEmission = 580 nm). Biochemische Steady-State-Experimente werden in PEM25-Puffer [25 mM Pipes-K+ (pH 6,8), 2 mM MgCl2, 1 mM EGTA] für Experimente mit Mikrotubuli durchgeführt. Der IC50 für die Steady-State-Hemmung wird bei 500 µM ATP, 5 µM Mikrotubuli und 1 nM KSP in PEM25-Puffer bestimmt. Ki app (scheinbare Inhibitor-Dissoziationskonstante)-Werte von Ispinesib (SB-715992) werden aus den Dosis-Wirkungs-Kurven extrahiert, mit expliziter Korrektur für die Enzymkonzentration unter Verwendung der Morrison-Gleichung. Die Inhibitor-Modalität (z. B. kompetitiv, nicht-kompetitiv, unkompetitiv oder gemischt) unter Steady-State-Bedingungen wird durch Messung des Effekts seiner Konzentration auf die Anfangsgeschwindigkeit als Funktion der Substratkonzentrationen bestimmt. Die Daten werden unter Verwendung von Gleichungen in GraFit an Geschwindigkeitsgleichungen für die verschiedenen Hemmungsmodi angepasst.
In vivo

Ispinesib (SB-715992) (4.5 mg/kg–15 mg/kg) exhibits inhibitory effects against Colo205, Colo201, HT-29, but not MX-1 cells, in mouse xenograft models. This compound (6 mg/kg–10 mg/kg) also inhibits murine solid tumors, including Madison 109 lung carcinoma, M5076 sarcoma, as well as L1210 and P388 leukemias. In mice xenograft models of breast cancer cells MCF-7, HCC1954, MDA-MB-468, and KPL4, it (8 mg/kg–10 mg/kg) inhibits tumor growth.

Referenzen
  • [4] https://pubmed.ncbi.nlm.nih.gov/20068098/

Informationen zu klinischen Studien (Clinical Trial Information)

(Daten von https://clinicaltrials.gov, aktualisiert am 2017-03-06)

NCT-Nummer Rekrutierung Bedingungen Sponsor/Kollaboratoren Startdatum Phases
NCT00095628 COMPLETED
Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
National Cancer Institute (NCI)
 2005-01 PHASE2
NCT00101244 TERMINATED
Adult Grade III Lymphomatoid Granulomatosis; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Splenic Marginal Zone Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Waldenström Macroglobulinemia
National Cancer Institute (NCI)
 2004-11 PHASE1
NCT00103311 COMPLETED
Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage IIIA Colon Cancer; Stage IIIA Rectal Cancer; Stage IIIB Colon Cancer; Stage IIIB Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Rectal Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer
National Cancer Institute (NCI)
 2005-01 PHASE2
NCT00607841 TERMINATED
Breast Neoplasms
Cytokinetics
 2007-12 PHASE1
NCT00363272 COMPLETED
Childhood Burkitt Lymphoma; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Spinal Cord Neoplasm; Childhood Supratentorial Ependymoma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Unspecified Childhood Solid Tumor, Protocol Specific
National Cancer Institute (NCI)
 2006-06 PHASE1
NCT00098826 COMPLETED
Acute Undifferentiated Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia
National Cancer Institute (NCI)
 2004-12 PHASE1