Home Cytoskeletal Signaling HSP Remmer BIIB021

alleen voor onderzoeksdoeleinden

BIIB021 HSP Remmer

Cat.nr.: S1175

BIIB021 (CNF2024) is een oraal beschikbaar, volledig synthetisch small-molecule remmer van HSP90 met een Ki en EC50 van respectievelijk 1,7 nM en 38 nM. Fase 2.
BIIB021 HSP Remmer Chemical Structure

Chemische structuur

Molecuulgewicht: 318.76

Spring naar

Kwaliteitscontrole (Quality Control)

Batch: Zuiverheid: 99.89%
99.89

Celkweek, behandeling & werkzame concentratie
(Cell Culture, Treatment & Working Concentration)

Cellijnen Assaytype Concentratie Incubatietijd Formulering Activiteitsbeschrijving PMID
MCF7 Function assay Inhibition of HSP90-mediated client protein HER2 degradation in human MCF7 cells, IC50=0.038μM 20055425
BT474 Function assay Binding affinity to Hsp90 nucleotide binding domain in human BT474 cells, IC50=0.14μM 20608738
MCF7 Function assay Inhibition of HSP90alpha in human MCF7 cells assessed as degradation of Her-2, EC50=0.038μM 22938030
NCI-H295 Cytotoxicity assay 120 mg/kg 5 days Cytotoxicity against human NCI-H295 cells overexpressing PGP xenografted in athymic mouse assessed as inhibition of tumor growth at 120 mg/kg, po qd for 5 days per week for 4 weeks 22938030
Sf9 Function assay 3 hrs Binding affinity to human N-terminal polyHis-tagged HSP90alpha (D9 to E236) alpha-helix conformation expressed in insect sf9 cells after 3 hrs by fluorescence polarization assay, Ki=0.002μM 24332488
Sf9 Function assay 3 hrs Binding affinity to human N-terminal polyHis-tagged HSP90beta (D9 to E236) expressed in insect sf9 cells after 3 hrs by fluorescence polarization assay, Ki=0.004μM 24332488
NCI-H1299 Function assay 12 hrs Reduction in oxygen consumption rate in human NCI-H1299 cells incubated for 12 hrs 25383915
HeLa Function assay 10 uM 6 hrs Inhibition of HSP90 in human HeLa cells assessed as induction of chk1 degradation at 10 uM after 6 hrs by Western blot method 28816449
HeLa Function assay 10 uM 6 hrs Inhibition of HSP90 in human HeLa cells assessed as induction of Akt degradation at 10 uM after 6 hrs by Western blot method 28816449
HeLa Function assay 10 uM 6 hrs Inhibition of HSP90 in human HeLa cells assessed as induction of HSP70 protein expression at 10 uM after 6 hrs by Western blot method 28816449
PC3 Function assay 10 uM 6 hrs Inhibition of HSP90 in human PC3 cells assessed as induction of chk1 degradation at 10 uM after 6 hrs by Western blot method 28816449
PC3 Function assay 10 uM 6 hrs Inhibition of HSP90 in human PC3 cells assessed as induction of Akt degradation at 10 uM after 6 hrs by Western blot method 28816449
PC3 Function assay 10 uM 6 hrs Inhibition of HSP90 in human PC3 cells assessed as induction of HSP70 protein expression at 10 uM after 6 hrs by Western blot method 28816449
TC32 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 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
SK-N-SH qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells 29435139
NB1643 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 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
Rh18 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 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
Rh41 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells 29435139
HCT116 Antiproliferative assay 48 hrs Antiproliferative activity against human HCT116 cells after 48 hrs by sulforhodamine B assay, GI50=0.15μM 29567459
A549 Antiproliferative assay 48 hrs Antiproliferative activity against human A549 cells after 48 hrs by sulforhodamine B assay, GI50=0.33μM 29567459
NCI-H1975 Antiproliferative assay 48 hrs Antiproliferative activity against human NCI-H1975 cells after 48 hrs by sulforhodamine B assay, GI50=0.38μM 29567459
HL60 Antiproliferative assay 48 hrs Antiproliferative activity against human HL60 cells after 48 hrs by sulforhodamine B assay, GI50=0.59μM 29567459
HL60 Function assay 1 uM 24 hrs Inhibition of HSP90 in human HL60 cells assessed as induction of HSP70 expression at 1 uM after 24 hrs by Western blot analysis 29567459
HL60 Function assay 1 uM 24 hrs Inhibition of HSP90 in human HL60 cells assessed as downregulation of phosphorylated Akt expression at 1 uM after 24 hrs by Western blot analysis 29567459
HL60 Function assay 1 uM 24 hrs Inhibition of HSP90 in human HL60 cells assessed as downregulation of phosphorylated STAT3 expression at 1 uM after 24 hrs by Western blot analysis 29567459
HL60 Function assay 1 uM 24 hrs Inhibition of HDAC in human HL60 cells assessed as upregulation of acetyl-alpha-tubulin levels at 1 uM after 24 hrs by Western blot analysis 29567459
HL60 Function assay 1 uM 24 hrs Inhibition of HDAC in human HL60 cells assessed as upregulation of acetylated histone H3 levels at 1 uM after 24 hrs by Western blot analysis 29567459
MCF7 Antiproliferative assay Antiproliferative activity against human MCF7 cells, IC50=0.31μM 31663736
Klik om meer experimentele gegevens over cellijnen te bekijken

Chemische informatie, opslag en stabiliteit (Chemical Information, Storage & Stability)

Molecuulgewicht 318.76 Formule

C14H15ClN6O

 Opslag (vanaf de datum van ontvangst)
CAS-nr. 848695-25-0 SDF downloaden Opslag van stamoplossingen

Synoniemen CNF2024 Smiles CC1=CN=C(C(=C1OC)C)CN2C=NC3=C2N=C(N=C3Cl)N

Oplosbaarheid (Solubility)

In vitro
Batch:

DMSO : 64 mg/mL (200.77 mM)
(Met vocht verontreinigd DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Ethanol : 12 mg/mL

Water : Insoluble

Molariteitscalculator

Massa Concentratie Volume Molecuulgewicht
Verdunningscalculator Molecuulgewichtcalculator

In vivo
Batch:

In vivo formulatiecalculator (heldere oplossing)

Stap 1: Voer onderstaande informatie in (Aanbevolen: een extra dier om rekening te houden met verlies tijdens het experiment)

mg/kg g μL

Stap 2: Voer de in vivo formulering in (Dit is alleen de calculator, geen formulering. Neem eerst contact met ons op als er geen in vivo formulering is in de sectie oplosbaarheid.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

Methode voor het bereiden van DMSO-moedervloeistof: mg geneesmiddel vooropgelost in μL DMSO ( Concentratie moedervloeistof mg/mL, Neem eerst contact met ons op als de concentratie de DMSO-oplosbaarheid van de batch van het geneesmiddel overschrijdt. )

Methode voor het bereiden van in vivo formulering: Neem μL DMSO moedervloeistof, voeg daarna toeμL PEG300, mengen en verhelderen, daarna toevoegenμL Tween 80, mengen en verhelderen, daarna toevoegen μL ddH2O, mengen en verhelderen.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO moedervloeistof, voeg daarna toe μL Maïsolie, mengen en verhelderen.

Opmerking: 1. Zorg ervoor dat de vloeistof helder is voordat u het volgende oplosmiddel toevoegt.
2. Zorg ervoor dat u het/de oplosmiddel(en) in de juiste volgorde toevoegt. U moet ervoor zorgen dat de verkregen oplossing, bij de vorige toevoeging, een heldere oplossing is voordat u verdergaat met het toevoegen van het volgende oplosmiddel. Fysieke methoden zoals vortexen, ultrasoon of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme (Mechanism of Action)

Targets/IC50/Ki
HSP90
(Cell-free assay)
1.7 nM(Ki)
In vitro
BIIB021 binds in the ATP-binding pocket of Hsp90, interferes with Hsp90 chaperone function, and results in client protein degradation and tumor growth inhibition. This compound inhibits tumor cell (BT474, MCF-7, N87, HT29, H1650, H1299, H69 and H82) proliferation with IC50 from 0.06-0.31 μM. It induces the degradation of Hsp90 client proteins including HER-2, Akt, and Raf-1 and up-regulated expression of the heat shock proteins Hsp70 and Hsp27. This chemical inhibits Hodgkin's lymphoma cells (KM-H2, L428, L540, L540cy, L591, L1236 and DEV) with IC50 from 0.24-0.8 μM. It shows low activity in lymphocytes from healthy individuals. This compound inhibits the constitutive activity of NF-κB despite defective IκB. It induces the expression of ligands for the activating NK cell receptor NKG2D on Hodgkin's lymphoma cells resulting in an increased susceptibility to NK cell–mediated killing. This chemical enhanced the in vitro radiosensitivity of HNSCCA cell lines (UM11B and JHU12) with a corresponding reduction in the expression of key radioresponsive proteins, increased apoptotic cells and enhance G2 arrest. It is considerably more active than 17-AAG against adrenocortical carcinoma H295R, both in vitro and in vivo. The cytotoxic activity of this compound is not influenced by loss of NQO1 or Bcl-2 overexpression, molecular lesions that do not prevent client loss but are nonetheless associated with reduced cell killing by 17-AAG. It is also active in 17-AAG resistant cell lines (NIH-H69, MES SA Dx5, NCI-ADR-RES, Nalm6 and etc.).
Kinase Assay
Hsp90 bindingsassay
Voor fluorescentiepolarisatie-competitiemetingen wordt de FITC-geldanamycine probe (20 nM) gedurende 3 uur gereduceerd met 2 mM TCEP bij kamertemperatuur, waarna de oplossing wordt gealiquoteerd en op -80 °C wordt bewaard tot gebruik. Recombinant humaan Hsp90α (0,8 nM) en gereduceerd FITC-geldanamycine (2 nM) worden gedurende 3 uur bij kamertemperatuur geïncubeerd in een 96-wells microplaat in aanwezigheid van assaybuffer die 20 mM HEPES (pH 7,4), 50 mM KCl, 5 mM MgCl2, 20 mM Na2MoO4, 2 mM DTT, 0,1 mg/mL BGG en 0,1% (v/v) CHAPS bevat. Na deze pre-incubatie wordt deze verbinding in 100% DMSO vervolgens toegevoegd tot eindconcentraties van 0,2 nM tot 10 μM (eindvolume 100 μL, 2% DMSO). De reactie wordt gedurende 16 uur bij kamertemperatuur geïncubeerd en de fluorescentie wordt vervolgens gemeten in een Analyst plaatlezer, excitatie = 485 nm, emissie = 535 nm. Hoge en lage controles bevatten respectievelijk geen van deze chemicaliën of geen Hsp90. De gegevens worden gefit aan een vierparametercurve en de IC50 wordt gegenereerd.
In vivo
Oral administration of BIIB021 leads to tumor growth inhibition in many tumor xenograft models including N87, BT474, CWR22, U87, SKOV3 and Panc-1. This compound effectively inhibits growth of L540cy tumor at a dose of 120 mg/kg. It significantly enhances antitumor growth effect of radiation in JHU12 xenograft.
Referenties
  • [4] https://pubmed.ncbi.nlm.nih.gov/19676042/

Informatie over klinische proeven (Clinical Trial Information)

(gegevens van https://clinicaltrials.gov, bijgewerkt op 2024-05-22)

NCT-nummer Werving Aandoeningen Sponsor/medewerkers Startdatum Fasen
NCT01017198 Completed
Advanced Solid Tumors
Biogen
 November 2009 Phase 1
NCT01004081 Completed
Breast Cancer
Biogen
 November 2009 Phase 2
NCT00618735 Completed
Advanced Solid Tumors
Biogen
 February 2008 Phase 1
NCT00618319 Completed
GIST
Biogen
 February 2008 Phase 2