Home Proteases Secretase inhibitor RO4929097 (RG-4733)

연구용

RO4929097 (RG-4733) γ-Secretase inhibitor

제품 번호: S1575

RO4929097 (RG-4733) is a γ secretase inhibitor with IC50 of 4 nM in a cell-free assay, inhibiting cellular processing of Aβ40 and Notch with EC50 of 14 nM and 5 nM, respectively. Phase 2.
RO4929097 (RG-4733) Secretase inhibitor Chemical Structure

화학 구조

분자량: 469.4

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품질 관리 (Quality Control)

배치: 순도: 99.77%
99.77

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

세포주 분석 유형 농도 배양 시간 제형 활성 설명 PMID
U87 Cell Viability Assay 30 μM 4 d decreases cell viability 24495907
U87 R1 Cell Viability Assay 30 μM 4 d decreases cell viability 24495907
MGG4 Cell Viability Assay 30 μM 4 d decreases cell viability 24495907
MGG6 Cell Viability Assay 30 μM 4 d decreases cell viability 24495907
MGG8 Cell Viability Assay 30 μM 4 d decreases cell viability 24495907
MGG23 Cell Viability Assay 30 μM 4 d decreases cell viability 24495907
SUM149 Cell Viability Assay 0-10 μM 72 h inhibits cell growth dose dependently 22547109
Sum190 Cell Viability Assay 0-10 μM 72 h inhibits cell growth dose dependently 22547109
WM35 Function Assay 10 uM 24 h DMSO decreases the levels of NOTCH downstream target HES1 21980408
WM98.1 Function Assay 10 uM 24 h DMSO decreases the levels of NOTCH downstream target HES1 21980408
WM115 Function Assay 10 uM 24 h DMSO decreases the levels of NOTCH downstream target HES1 21980408
WM983A Function Assay 10 uM 24 h DMSO decreases the levels of NOTCH downstream target HES1 21980408
WM3248  Function Assay 10 uM 24 h DMSO decreases the levels of NOTCH downstream target HES1 21980408
WM35 Growth Inhibition Assay 10 uM 0-18 d DMSO inhibits cell growth time dependently 21980408
WM98.1 Growth Inhibition Assay 10 uM 0-18 d DMSO inhibits cell growth time dependently 21980408
WM115 Growth Inhibition Assay 10 uM 0-18 d DMSO inhibits cell growth time dependently 21980408
WM983A Growth Inhibition Assay 10 uM 0-18 d DMSO inhibits cell growth time dependently 21980408
WM3248  Growth Inhibition Assay 10 uM 0-18 d DMSO inhibits cell growth time dependently 21980408
A673 qHTS assay 29435139
DAOY qHTS assay 29435139
BT-37 qHTS assay 29435139
BT-12 qHTS assay 29435139
OHS-50 qHTS assay 29435139
SJ-GBM2 qHTS assay 29435139
SK-N-MC qHTS assay 29435139
NB-EBc1 qHTS assay 29435139
LAN-5 qHTS assay 29435139
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화학 정보, 보관 및 안정성 (Chemical Information, Storage & Stability)

분자량 469.4 화학식

C22H20F5N3O3

 보관 (수령일로부터)
CAS 번호 847925-91-1 SDF 다운로드 원액 보관

동의어 RG-4733 Smiles CC(C)(C(=O)NCC(C(F)(F)F)(F)F)C(=O)NC1C2=CC=CC=C2C3=CC=CC=C3NC1=O

용해도 (Solubility)

In vitro
배치:

DMSO : 94 mg/mL (200.25 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Ethanol : 50 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
γ secretase
(Cell-free assay)
4 nM
Notch
(Cell-free assay)
5 nM
Aβ40
(Cell-free assay)
14 nM
시험관 내(In vitro)
RO4929097 decreases the amount of Aβ peptides secreted into the culture medium in HEK293 cells with EC50 of 14 nM. This compound strongly inhibits Notch processing with EC50 of 5 nM in the Notch cell-based reporter assay. The potency of this chemical in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity observed with respect to 75 other proteins of various types including receptors, ion channels, and enzymes (CEREP panel). After 5 days of treatment, it reduces the production of ICN in the human NSCLC A549 cells inducing a flattened and less transformed tumor cell phenotype in tissue culture. It blocks Notch processing in human non-small cell lung carcinoma cells and decreases expression of the Notch transcriptional target gene Hes1. Treatment with this compound reveals a two- to threefold decrease in the expression of direct Notch target genes, Hes1, Hey1, and Heyl in SUM149 and a 3.5- to eightfold decrease in expression in SUM190 cells. It modestly inhibits the growth of SUM149 cells in a dose-dependent manner. At a concentration of 1 μM of this chemical, growth inhibition is 20 % for SUM149 and 10 % for SUM190 cells, relative to vehicle-treated controls. It decreases the production of inflammatory cytokines by T-cells. Furthermore, with this treatment, there is a shift in favor of TH2 over TH1 cytokines. In addition, T-cell activation induced IL-6 production would be increased with this compound. Upon this treatment, the selected melanoma cell lines reveals downregulation of NOTCH downstream effector HES1. A decrease in the amount of melanospheres formed upon this treatment in primary melanoma cell lines is detected.
키나아제 분석
In vitro potency assays
After RO4929097 is used, the Aβ peptides are measured by ECL assays using a variety of anti-Aβ antibodies and an Origen 1.5 Analyzer. The 4G8 murine mAb binds an epitope in the Aβ peptide (within amino acids 18–21) that is immediately distal to the α-secretase cleavage site. The G2–10 murine mAb binds the C terminus that is exposed after γ-secretase-mediated cleavage to generate amino acid 40 of the Aβ40 peptide. The FCA3542 rabbit antibody binds the C terminus that is exposed after γ-secretase-mediated cleavage to generate amino acid 42 of the Aβ42 peptide. The 4G8 mAb is biotinylated with biotin-LC-sulfo-N-hydroxysuccinimide-ester. The G2–10 and FCA3542 antibodies are ruthenylated with TAG-N-hydroxysuccinimide ester. Aβ(x-40) is detected with biotinylated 4G8 and ruthenylated G2–10. Aβ(x-42) is detected with biotinylated 4G8 and ruthenylated FCA3542.
생체 내(In vivo)
Oral injection of 3 to 60 mg/kg RO4929097 once daily or twice daily to nude mice bearing A549 NSCLC xenografts for either 7, 14, or 21 days of a 21-day schedule results in significant tumor growth inhibition compared with vehicle-treated animals. The tumor growth inhibition values ranges from 66% to 91%. When mice are treated with 60 mg/kg of this compound twice daily with the 7+/14- schedule, treatment initially arouses regression of established A549 tumors. At the end of the 21-day cycle (day 47), tumor growth prevention is still 91% compared with vehicle control mice. Inhibition of tumor growth remains prolonged and sustained up to 34 days post-treatment (day 67). On day 67, these mice are retreated with the same dose of this chemical for a second cycle (7 days) until day 74. Importantly, the antitumor effects are sustained after dosing is completed. This compound leads to reduced expression of genes associated with angiogenesis in A549 xenograft model. In contrast, the RO4929097-resistant H460a xenograft displays little change in expression of these genes, underscoring the in vivo anti-angiogenesis mechanism of action of this agent. For IL6 and IL8 overexpressing tumors, it no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts.
참조
  • [4] https://pubmed.ncbi.nlm.nih.gov/21315665/
  • [5] https://pubmed.ncbi.nlm.nih.gov/10801983/

적용 분야 (Applications)

방법 바이오마커 이미지 PMID
Western blot Hey1 Snail / N-cadherin / Twist / E-cadherin Akt / p-Akt / Notch / IGF1R / FBXW7 NICD / Hes1 / Hes3 / Hes5
S1575-WB1
29899322
Growth inhibition assay Cell viability
S1575-viability1
30669546

자주 묻는 질문 (Frequently Asked Questions)

질문 1:
How about its half-life?

답변:
Its half-life is about 20 hours based on the following paper: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869895/