Home Cytoskeletal Signaling HSP 억제제 BIIB021

연구용

BIIB021 HSP 억제제

제품 번호: S1175

BIIB021 (CNF2024)은 HSP90의 경구 투여가 가능한 완전 합성 소분자 억제제로, Ki 및 EC50은 각각 1.7 nM 및 38 nM입니다. 임상 2상.
BIIB021 HSP 억제제 Chemical Structure

화학 구조

분자량: 318.76

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품질 관리 (Quality Control)

배치: 순도: 99.89%
99.89

세포 배양, 처리 및 작업 농도
(Cell Culture, Treatment & Working Concentration)

세포주 분석 유형 농도 배양 시간 제형 활성 설명 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
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화학 정보, 보관 및 안정성 (Chemical Information, Storage & Stability)

분자량 318.76 화학식

C14H15ClN6O

 보관 (수령일로부터)
CAS 번호 848695-25-0 SDF 다운로드 원액 보관

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

용해도 (Solubility)

In vitro
배치:

DMSO : 64 mg/mL (200.77 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Ethanol : 12 mg/mL

Water : Insoluble

몰농도 계산기

질량 농도 부피 분자량
희석 계산기 분자량 계산기

In vivo
배치:

생체 내 제형 계산기 (투명한 용액)

1단계: 아래 정보 입력 (권장: 실험 중 손실을 고려하여 추가 동물 포함)

mg/kg g μL

2단계: 생체 내 제형 입력 (이것은 계산기일 뿐 제형이 아닙니다. 용해도 섹션에 생체 내 제형이 없는 경우 먼저 당사에 문의하십시오.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

계산 결과:

작업 농도: mg/ml;

DMSO 원액 준비 방법: mg 약물 사전 용해 μL DMSO ( 원액 농도 mg/mL, 농도가 해당 약물 배치의 DMSO 용해도를 초과하는 경우 먼저 당사에 문의하십시오. )

생체 내 제형 준비 방법: 취하다 μL DMSO 원액, 다음 추가μL PEG300, 혼합하고 투명하게 한 다음 추가μL Tween 80, 혼합하고 투명하게 한 다음 추가 μL ddH2O, 혼합하고 투명하게 합니다.

생체 내 제형 준비 방법: 취하다 μL DMSO 원액, 다음 추가 μL 옥수수 기름, 혼합하고 투명하게 합니다.

참고: 1. 다음 용매를 추가하기 전에 액체가 투명한지 확인하십시오.
2. 용매를 순서대로 추가해야 합니다. 다음 용매를 추가하기 전에 이전 추가에서 얻은 용액이 투명한 용액인지 확인해야 합니다. 와동, 초음파 또는 뜨거운 물 중탕과 같은 물리적 방법을 사용하여 용해를 도울 수 있습니다.

작용 메커니즘 (Mechanism of Action)

Targets/IC50/Ki
HSP90
(Cell-free assay)
1.7 nM(Ki)
시험관 내(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.).
키나아제 분석
HSP90 결합 분석
형광 편광 경쟁 측정을 위해 FITC-geldanamycin 프로브(20 nM)를 실온에서 3시간 동안 2 mM TCEP로 환원시킨 후, 용액을 분주하여 사용 전까지 -80 °C에 보관합니다. 재조합 인간 Hsp90α(0.8 nM)와 환원된 FITC-geldanamycin(2 nM)을 20 mM HEPES(pH 7.4), 50 mM KCl, 5 mM MgCl2, 20 mM Na2MoO4, 2 mM DTT, 0.1 mg/mL BGG 및 0.1%(v/v) CHAPS를 포함하는 분석 완충액 존재 하에서 96웰 마이크로플레이트에 넣고 실온에서 3시간 동안 배양합니다. 이 사전 배양 후, 100% DMSO에 녹인 이 화합물을 0.2 nM에서 10 μM의 최종 농도가 되도록 첨가합니다(최종 부피 100 μL, 2% DMSO). 반응물을 실온에서 16시간 동안 배양한 후 Analyst 플레이트 리더(여기 = 485 nm, 방출 = 535 nm)에서 형광을 측정합니다. 높은 대조군과 낮은 대조군에는 각각 이 화학 물질이 없거나 Hsp90이 없는 샘플이 포함되었습니다. 데이터는 4-파라미터 곡선에 피팅되었으며 IC50이 산출되었습니다.
생체 내(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.
참조
  • [4] https://pubmed.ncbi.nlm.nih.gov/19676042/

임상시험 정보 (Clinical Trial Information)

(데이터 출처 https://clinicaltrials.gov, 업데이트 날짜 2024-05-22)

NCT 번호 모집 조건 스폰서/협력자 시작일 단계
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Advanced Solid Tumors
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Breast Cancer
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 November 2009 Phase 2
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Advanced Solid Tumors
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GIST
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 February 2008 Phase 2