Home Cytoskeletal Signaling HSP Hämmare BIIB021

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BIIB021 HSP Hämmare

Kat.nr.: S1175

BIIB021 (CNF2024) är en oralt tillgänglig, helsyntetisk småmolekylär hämmare av HSP90 med Ki och EC50 på 1,7 nM respektive 38 nM. Fas 2.
BIIB021 HSP Hämmare Chemical Structure

Kemisk struktur

Molekylvikt: 318.76

Hoppa till

Kvalitetskontroll (Quality Control)

Batch: Renhet: 99.89%
99.89

Cellodling, behandling & arbetskoncentration
(Cell Culture, Treatment & Working Concentration)

Cellinjer Analystyp Koncentration Inkubationstid Formulering Aktivitetsbeskrivning 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
Klicka för att visa mer experimentella data för cellinjer

Kemisk information, lagring & stabilitet (Chemical Information, Storage & Stability)

Molekylvikt 318.76 Formel

C14H15ClN6O

 Lagring (från mottagningsdatumet)
CAS-nr 848695-25-0 Ladda ner SDF Lagring av stamlösningar

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

Löslighet (Solubility)

In vitro
Batch:

DMSO : 64 mg/mL (200.77 mM)
(Fuktkontaminerad DMSO kan minska lösligheten. Använd färk, vattenfri DMSO.)

Ethanol : 12 mg/mL

Water : Insoluble

Molaritetsräknare

Massa Koncentration Volym Molekylvikt
Utspädningsräknare Molekylviktsräknare

In vivo
Batch:

In vivo-formuleringsräknare (Klar lösning)

Steg 1: Ange information nedan (Rekommenderas: Ett extra djur för att ta hänsyn till förluster under experimentet)

mg/kg g μL

Steg 2: Ange in vivo-formuleringen (Detta är endast räknaren, inte formuleringen. Vänligen kontakta oss först om det inte finns någon in vivo-formulering i löslighetsavsnittet.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Beräkningsresultat:

Arbetskoncentration: mg/ml;

Metod för att bereda DMSO-stamlösning: mg substans förlöst i μL DMSO ( Stamlösningskoncentration mg/mL, Vänligen kontakta oss först om koncentrationen överskrider DMSO-lösligheten för denna batch av substansen. )

Metod för att bereda in vivo-formulering: Ta μL DMSO stamlösning, tillsätt sedanμL PEG300, blanda och klarna, tillsätt sedanμL Tween 80, blanda och klarna, tillsätt sedan μL ddH2O, blanda och klarna.

Metod för att bereda in vivo-formulering: Ta μL DMSO stamlösning, tillsätt sedan μL Majsolja, blanda och klarna.

Obs: 1. Se till att vätskan är klar innan du tillsätter nästa lösningsmedel.
2. Se till att tillsätta lösningsmedlet/lösningsmedlen i ordning. Du måste se till att lösningen som erhålls i föregående tillsats är en klar lösning innan du fortsätter att tillsätta nästa lösningsmedel. Fysiska metoder som vortex, ultraljud eller varmt vattenbad kan användas för att underlätta upplösningen.

Verkningsmekanism (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.).
Kinasanalys
Hsp90-bindningsanalys
För fluorescenspolarisationstävlingsmätningar reduceras FITC-geldanamycinproben (20 nM) med 2 mM TCEP vid rumstemperatur i 3 timmar, varefter lösningen alikvoteras och förvaras vid -80 °C tills den används. Rekombinant humant Hsp90α (0,8 nM) och reducerat FITC-geldanamycin (2 nM) inkuberas i en 96-brunns mikroplatta vid rumstemperatur i 3 timmar i närvaro av analysbuffert innehållande 20 mM HEPES (pH 7,4), 50 mM KCl, 5 mM MgCl2, 20 mM Na2MoO4, 2 mM DTT, 0,1 mg/mL BGG och 0,1 % (v/v) CHAPS. Efter denna förinkubation tillsätts denna kemikalie i 100 % DMSO till slutkoncentrationer på 0,2 nM till 10 μM (slutvolym 100 μL, 2 % DMSO). Reaktionen inkuberas i 16 timmar vid rumstemperatur och fluorescensen mäts sedan i en Analyst-plattläsare, excitation = 485 nm, emission = 535 nm. Höga och låga kontroller innehöll ingen av denna kemikalie respektive inget Hsp90. Data anpassas till en fyrapunktsparameterkurva och IC50 genereras.
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.
Referenser
  • [4] https://pubmed.ncbi.nlm.nih.gov/19676042/

Klinisk prövningsinformation (Clinical Trial Information)

(data från https://clinicaltrials.gov, uppdaterad den 2024-05-22)

NCT-nummer Rekrytering Tillstånd Sponsor/Samarbetspartners Startdatum Faser
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