Home TGF-beta/Smad TGF-beta/Smad inhibitor Galunisertib (LY2157299)

연구용

Galunisertib (LY2157299) TGF-beta/Smad inhibitor

제품 번호: S2230

Galunisertib (LY2157299) is a potent TGFβ receptor I (TβRI / ALK5) inhibitor with IC50 of 56 nM in a cell-free assay. Phase 2/3.
Galunisertib (LY2157299) TGF-beta/Smad inhibitor Chemical Structure

화학 구조

분자량: 369.42

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품질 관리 (Quality Control)

배치: 순도: 99.99%
99.99

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

세포주 분석 유형 농도 배양 시간 제형 활성 설명 PMID
Panc-1 Function Assay 10 μM 48 h DMSO stimulates the cell invasion into the collagen gel and the Matrigel-coated collagen gel 24780821
Sf9 Function assay Inhibition of human recombinant GST-fused ALK5 expressed in Sf9 insect cells using casein as substrate by proprietary radioisotopic protein kinase assay, IC50 = 0.0694 μM. 26483198
Sf9 Function assay Inhibition of human ALK5 expressed in Sf9 insect cells using casein as substrate in presence of [gamma-33P]ATP, IC50 = 0.051 μM. 28135685
Sf9 Function assay 1 hr Inhibition of human His-tagged TGFbetaR1 T204D mutant expressed in Sf9 insect cells after 1 hr by HTRF assay, IC50 = 0.0041 μM. 29422332
B16 Antitumor assay 75 mg/kg Antitumor activity against mouse B16 cells in mouse assessed as inhibition of tumor growth at 75 mg/kg, po bid relative to vehicle-treated control 24786585
B16 Antitumor assay 75 mg/kg Antitumor activity against mouse B16 cells in mouse assessed as suppression of tumor volume at 75 mg/kg, po bid relative to vehicle-treated control 24786585
B16 Antitumor assay 75 mg/kg Antitumor activity against mouse B16 cells in mouse assessed as inhibition of lymph node metastasis at 75 mg/kg, po bid relative to vehicle-treated control 24786585
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화학 정보, 보관 및 안정성 (Chemical Information, Storage & Stability)

분자량 369.42 화학식

C22H19N5O

 보관 (수령일로부터)
CAS 번호 700874-72-2 SDF 다운로드 원액 보관

동의어 N/A Smiles CC1=NC(=CC=C1)C2=NN3CCCC3=C2C4=C5C=C(C=CC5=NC=C4)C(=O)N

용해도 (Solubility)

In vitro
배치:

DMSO : 74 mg/mL (200.31 mM)
(수분으로 오염된 DMSO는 용해도를 감소시킬 수 있습니다. 신선하고 무수 DMSO를 사용하십시오.)

Water : Insoluble

Ethanol : 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
TβRI
(Cell-free assay)
56 nM
시험관 내(In vitro)

Galunisertib (LY2157299) potently inhibits the TGFβ receptor signaling. It abolishes the TGFβ induced Smad2 phosphorylation in HUVEC cells, and also shows dose dependent potentiation of VEGF or bFGF induced cell proliferation in HUVEC. This compound promotes VEGF induced HUVEC cell migration and potentiates angiogenesis in the in vitro VEGF-stimulated cord formation assay.It inhibits TGF-β-mediated SMAD2 activation and hematopoietic suppression in primary hematopoietic stem cells in a dose-dependent manner. LY2157199 treatment stimulates hematopoiesis from primary MDS bone marrow specimens.In human glioblastoma (GBM) cells, it blocks signaling through the heteromeric TGFβ receptor complex to reduce levels of active, phosphorylated SMAD.
키나아제 분석
TGF-β Type I (RIT204D) Receptors reaction
Reactions: 170-200 nM enzyme in 1 × KB (50 mM Tris pH 7.5, 150 mM NaCl, 4 mM MgCl2, 1 mM NaF, 2 mM β-mercaptoethanol), with a dilution series of Galunisertib (LY2157299) in 1 × KB /16% DMSO (20 μM to 1 nM final concentration with 4% DMSO final concentration). Reactions are started by adding ATP mix (4 μM ATP/ 1 μCi 33P-α-ATP final concentrations) in 1 × KB. Reactions are incubated at 30 °C for 1 hour. Reactions are stopped and quantitated using standard TCA/BSA precipitation onto Millipore FB glass fiber filter plates and by liquid scintillation counting on a MicroBeta JET.
생체 내(In vivo)

Although anti-tumor activity has been observed in several pre-clinical models, Galunisertib (LY2157299) fails to show significant in vivo angiogenic effects in the 4T1, Colo205, or A549 xenograft models.

Administration of this compound ameliorates anemia in a TGF-β overexpressing transgenic mouse model of bone marrow failure.

Oral administration of it at 75 mg/kg/day displays significant antitumor activity against both Calu6 and MX1 xenografts in mice.

In vivo, it induces angiogenesis and enhances VEGF and basic-fibroblast-growth-factor-induced angiogenesis in a Matrigel-plug assay, whereas adding an alpha5-integrin-neutralizing antibody to the Matrigel selectively inhibits this enhanced response.
참조
  • [4] http://mct.aacrjournals.org/cgi/content/short/10/11_MeetingAbstracts/C201?rss=1
  • [5] https://pubmed.ncbi.nlm.nih.gov/18039567/
  • [6] https://pubmed.ncbi.nlm.nih.gov/19706683/
  • [7] https://pubmed.ncbi.nlm.nih.gov/35342344/

적용 분야 (Applications)

방법 바이오마커 이미지 PMID
Western blot Periostin / Fibronectin / Snail / Twist / pSmad2 / pERK / pAkt / pFAK TGF-βR1 / p-ERK
S2230-WB1
29774119
Growth inhibition assay Cell viability
S2230-viability1
28873435
Immunofluorescence E-cadherin
S2230-IF1
29467918

임상시험 정보 (Clinical Trial Information)

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

NCT 번호 모집 조건 스폰서/협력자 시작일 단계
NCT04031872 Unknown status
Colorectal Cancer Metastatic
The Netherlands Cancer Institute|Vall d''Hebron Institute of Oncology|Agendia|European Organisation for Research and Treatment of Cancer - EORTC|Azienda Ospedaliera Niguarda Cà Granda|Fundación para la Investigación del Hospital Clínico de Valencia|University of Campania Luigi Vanvitelli|University of Turin Italy|Eli Lilly and Company|Catalan Institute of Health|Universitaire Ziekenhuizen KU Leuven
 February 2020 Phase 1|Phase 2
NCT03470350 Withdrawn
Colorectal Cancer Metastatic
The Netherlands Cancer Institute|Vall d''Hebron Institute of Oncology|Agendia|European Organisation for Research and Treatment of Cancer - EORTC|Azienda Ospedaliera Niguarda Cà Granda|Fundación para la Investigación del Hospital Clínico de Valencia|University of Campania Luigi Vanvitelli|University of Turin Italy|Eli Lilly and Company|Catalan Institute of Health|Universitaire Ziekenhuizen KU Leuven
 August 24 2018 Phase 1|Phase 2
NCT02734160 Completed
Metastatic Pancreatic Cancer
Eli Lilly and Company|AstraZeneca
 June 15 2016 Phase 1
NCT02452008 Recruiting
Prostate Cancer
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins|Eli Lilly and Company
 May 3 2016 Phase 2
NCT02752919 Completed
Healthy
Eli Lilly and Company
 April 2016 Phase 1