Home Protein Tyrosine Kinase ALK inhibitor Alectinib (CH5424802)

연구용

Alectinib (CH5424802) ALK inhibitor

제품 번호: S2762

Alectinib is a potent ALK inhibitor with IC50 of 1.9 nM in cell-free assays, sensitive to L1196M mutation and higher selectivity for ALK than PF-02341066, NVP-TAE684 and PHA-E429.
Alectinib (CH5424802) ALK inhibitor Chemical Structure

화학 구조

분자량: 482.62

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품질 관리 (Quality Control)

배치: 순도: 99.95%
99.95

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

세포주 분석 유형 농도 배양 시간 제형 활성 설명 PMID
NCI-H2228 Kinase assay ~1 μM prevents autophosphorylation of ALK 21575866
KARPAS-299 Growth inhibitory assay ~10 μM IC50=3 nM 21575866
SR Growth inhibitory assay ~10 μM IC50=6.9 nM 21575866
HDLM-2 Growth inhibitory assay ~10 μM IC50>10,000 nM 21575866
NB-1 Growth inhibitory assay ~10 μM IC50=4.5 nM 21575866
KELLY Growth inhibitory assay ~10 μM IC50=62 nM 21575866
SK-N-FI Growth inhibitory assay ~10 μM IC50>10,000 nM 21575866
NCI-H2228 Growth inhibitory assay ~10 μM IC50=53 nM 21575866
Calu-3 Growth inhibitory assay ~10 μM IC50=>10,000 nM 21575866
PC-1 Growth inhibitory assay ~10 μM IC50>10,000 nM 21575866
NCI-H23 Growth inhibitory assay ~10 μM IC50=3600 nM 21575866
Calu-1 Growth inhibitory assay ~10 μM IC50>10,000 nM 21575866
NCI-H2009 Growth inhibitory assay ~10 μM IC50>10,000 nM 21575866
NCI-H1993 Growth inhibitory assay ~10 μM IC50>10,000 nM 21575866
MKN-45 Growth inhibitory assay ~10 μM IC50>10,000 nM 21575866
SNU-5 Growth inhibitory assay ~10 μM IC50=1800 nM 21575866
KATO-III Growth inhibitory assay ~10 μM IC50=7900 nM 21575866
SK-BR-3 Growth inhibitory assay ~10 μM IC50>10,000 nM 21575866
BT-483 Growth inhibitory assay ~10 μM IC50>10,000 nM 21575866
PC-3 Growth inhibitory assay ~10 μM IC50>10,000 nM 21575866
22Rv1 Growth inhibitory assay ~10 μM IC50>10,000 nM 21575866
U-87 MG Growth inhibitory assay ~10 μM IC50>10,000 nM 21575866
H3122 Growth inhibitory assay ~10 μM IC50=33 nM 25096400
LC-2/ad Apoptosis assay ~1 μM DMSO induces apoptosis 25349307
LC-2/ad Function assay ~1 μM DMSO inhibits the MAPK signaling pathway 25349307
Ba/F3 Function assay ~1 μM DMSO suppresses phosphorylation of ERK and increases the abundance of BIM 25349307
SNU-2535 Growth inhibitory assay ~10 μM IC50=33.1 nM 26849637
SNU-2535 Kinase assay ~1 μM inhibits the phosphorylation of ALK and its downstream molecules ERK1/2 and AKT 26849637
Ba/F3 Function assay 72 hrs Inhibition of EML4-ALK C1156Y mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.002 μM. 26568289
Ba/F3 Function assay 72 hrs Inhibition of EML4-ALK S1206Y mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.002 μM. 26568289
Ba/F3 Function assay 72 hrs Inhibition of wild type EML4-ALK (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.002 μM. 26568289
KARPAS299 Antiproliferative assay 96 hrs Antiproliferative activity against human KARPAS299 cells after 96 hrs by cell counting assay, IC50 = 0.003 μM. 22225917
Ba/F3 Function assay 72 hrs Inhibition of EML4-ALK F1174L mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.003 μM. 26568289
Ba/F3 Function assay 72 hrs Inhibition of EML4-ALK G1269A mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.009 μM. 26568289
NCI-H3122 Antiproliferative assay 72 hrs Antiproliferative activity against human NCI-H3122 cells after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.009 μM. 26568289
KARPAS299 Antiproliferative assay 72 hrs Antiproliferative activity against human KARPAS299 cells after 72 hrs by SRB/CCK-8 assay, IC50 = 0.015 μM. 27131066
NCI-H3122 Antiproliferative assay 72 hrs Antiproliferative activity against human NCI-H3122 cells after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0174 μM. 27131066
SUP-M2 Antiproliferative assay 72 hrs Antiproliferative activity against human SUP-M2 cells after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0179 μM. 27131066
NCI-H3122 Function assay 72 hrs Inhibition of ALK expressed in human NCI-H3122 cells assessed as cell growth inhibition after 72 hrs by SRB/CCK-8 assay, IC50 = 0.019 μM. 27131066
NCI-H3122 Antiproliferative assay 72 hrs Antiproliferative activity against ALK-dependent human NCI-H3122 cells after 72 hrs, IC50 = 0.019 μM. 26476749
SU-DHL1 Antiproliferative assay 72 hrs Antiproliferative activity against human SU-DHL1 cells after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0205 μM. 27131066
NIH/3T3 Antiproliferative assay 72 hrs Antiproliferative activity against mouse NIH/3T3 cells expressing wild type EML4-ALK after 72 hrs by SRB/CCK-8 assay, IC50 = 0.0323 μM. 27131066
Ba/F3 Function assay 72 hrs Inhibition of EML4-ALK 1151Tins mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.072 μM. 26568289
Ba/F3 Function assay 72 hrs Inhibition of EML4-ALK L1196M mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.09 μM. 26568289
NIH/3T3 Antiproliferative assay 72 hrs Antiproliferative activity against mouse NIH/3T3 cells expressing EML4-ALK L1196 mutant after 72 hrs by SRB/CCK-8 assay, IC50 = 0.132 μM. 27131066
Ba/F3 Function assay 72 hrs Inhibition of EML4-ALK L1152R mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.169 μM. 26568289
Ba/F3 Function assay 72 hrs Inhibition of EML4-ALK G1202R mutant (unknown origin) expressed in mouse Ba/F3 cells assessed as cell viability after 72 hrs by MTS assay, IC50 = 0.207 μM. 26568289
DFCI114 Antiproliferative assay 72 hrs Antiproliferative activity against human DFCI114 cells expressing EML4-ALK G1269A mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.207 μM. 26568289
CHLA20 Antiproliferative assay 72 hrs Antiproliferative activity against human CHLA20 cells expressing EML4-ALK R1275Q mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.43 μM. 26568289
Kelly Antiproliferative assay 72 hrs Antiproliferative activity against human Kelly cells expressing EML4-ALK F1174L mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.434 μM. 26568289
DFCI76 Antiproliferative assay 72 hrs Antiproliferative activity against human DFCI76 cells expressing EML4-ALK L1152R mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.511 μM. 26568289
LAN5 Antiproliferative assay 72 hrs Antiproliferative activity against human LAN5 cells expressing EML4-ALK R1275Q mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.617 μM. 26568289
SMS-KCNR Antiproliferative assay 72 hrs Antiproliferative activity against human SMS-KCNR cells expressing EML4-ALK R1275Q mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.765 μM. 26568289
SK-N-SH Antiproliferative assay 72 hrs Antiproliferative activity against human SK-N-SH cells expressing EML4-ALK F1174L mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 0.872 μM. 26568289
SH-SY5Y Antiproliferative assay 72 hrs Antiproliferative activity against human SH-SY5Y cells expressing EML4-ALK F1174L mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 1.15 μM. 26568289
SK-N-BE(2) Antiproliferative assay 72 hrs Antiproliferative activity against human SK-N-BE(2) cells expressing wild type EML4-ALK after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 1.554 μM. 26568289
LAN1 Antiproliferative assay 72 hrs Antiproliferative activity against human LAN1 cells expressing EML4-ALK F1174L mutant after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 2.004 μM. 26568289
SK-N-AS Antiproliferative assay 72 hrs Antiproliferative activity against human SK-N-AS cells expressing wild type EML4-ALK after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 2.139 μM. 26568289
SK-N-FI Antiproliferative assay 72 hrs Antiproliferative activity against human SK-N-FI cells expressing wild type EML4-ALK after 72 hrs by CellTiter-Glo Luminescent Cell Viability Assay, EC50 = 2.401 μM. 26568289
NIH/3T3 Antitumor assay 50 mg/kg 10 days Antitumor activity against mouse NIH/3T3 cells expressing EML4-ALK L1196M mutant xenografted in nude mouse assessed as tumor stasis at 50 mg/kg, po qd administered for 10 days 27131066
NIH/3T3 Antitumor assay 50 mg/kg 10 days Antitumor activity against mouse NIH/3T3 cells expressing EML4-ALK L1196M mutant xenografted in nude mouse assessed as partial tumor regression at 50 mg/kg, po qd administered for 10 days 27131066
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화학 정보, 보관 및 안정성 (Chemical Information, Storage & Stability)

분자량 482.62 화학식

C30H34N4O2

 보관 (수령일로부터)
CAS 번호 1256580-46-7 SDF 다운로드 원액 보관

동의어 AF-802, RG-7853,CH5424802 Smiles CCC1=CC2=C(C=C1N3CCC(CC3)N4CCOCC4)C(C5=C(C2=O)C6=C(N5)C=C(C=C6)C#N)(C)C

용해도 (Solubility)

In vitro
배치:

DMSO : 7 mg/mL (14.5 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
ALK (F1174L)
(Cell-free assay)
1 nM
ALK
(Cell-free assay)
1.9 nM
ALK (R1275Q)
(Cell-free assay)
3.5 nM
시험관 내(In vitro)
The dissociation constant (KD) value of CH5424802 for ALK in an ATP-competitive manner is 2.4 nM. CH5424802 has substantial inhibitory potency against both native ALK and L1196M with Ki of 0.83 nM and 1.56 nM, respectively. CH5424802 prevents autophosphorylation of ALK in NCI-H2228 NSCLC cells expressing EML4-ALK. CH5424802 also suppresses the phosphorylation of STAT3 and AKT, but not of ERK1/2. CH5424802 completely inhibits the phosphorylation of STAT3 at Tyr705. CH5424802 is preferentially efficacious against NCI-H2228 cells expressing EML4-ALK, but not ALK fusion-negative NSCLC cell lines, including HCC827 cells (EGFR exon 19 deletion), A549 cells (KRAS mutant), or NCI-H522 cells (EGFR wild-type, KRAS wild-type, and ALK wild-type) in monolayer culture. CH5424802 elicits an apoptotic marker—caspase-3/7-like activation—in NCI-H2228 spheroid cells. CH5424802 blocks the growth of two lymphoma lines, KARPAS-299 and SR, with NPM-ALK fusion protein but does not influence the growth of an HDLM-2 lymphoma line without ALK fusion. CH5424802 displays high target selectivity and the stronger anti-proliferative activity against KARPAS-299. CH5424802 inhibits KAPRAS-299 with an IC50 of 3 nM, and KDR with IC50 of 1.4 μM. The metabolic stability of CH5424802 is very high.
키나아제 분석
Kinase inhibitory assays in Vitro
The inhibitory ability against each kinase except for MEK1 and Raf-1 is evaluated by examining their ability to phosphorylate various substrate peptides in the presence of CH5424802 using time-resolved fluorescence resonance energy transfer (TR-FRET) assay or fluorescence polarization (FP) assay. The inhibitory activity against MEK1 is evaluated by quantitative analysis of the phosphorylation of a substrate peptide by a recombinant ERK2 protein in the presence of CH5424802. The inhibitory activity against Raf-1 is evaluated by examining the ability of the kinases to phosphorylate MEK1 in the presence of CH5424802.
생체 내(In vivo)
Oral administration of CH5424802 dose-dependently inhibits tumor growth with an ED50 of 0.46 mg/kg and tumor regression. Treatment of 20 mg/kg CH5424802 reveals rapid tumor regression by 168%, the tumor volume in any mouse is <30 mm3 after 11 days of treatment (at day 28), a potent antitumor effect is maintained, and tumor regrowth does not occur throughout the 4-week drug-free period. The half-life and the oral bioavailability of CH5424802 in mice are 8.6 hours and 70.8%, respectively. At a repeated dose of 6 mg/kg, the mean plasma levels reached 1.7, 1.5, and 0.3 nM at 2, 7, and 24 hours post-dose, respectively. Administration of CH5424802 leads to tumor growth prevention and tumor regression. Tumor growth inhibition at 20 mg/kg is 119% for KARPAS-299 and 104% for NB-1 on day 20. CH5424802 inhibits the phosphorylation of STAT3 in a dose-dependent manner (2–20 mg/kg). A partial decrease in AKT phosphorylation is also observed in CH5424802-treated xenograft tumors.
참조

적용 분야 (Applications)

방법 바이오마커 이미지 PMID
Western blot pALK / ALK / pAKT / AKT / pERK / ERK / pS6 / S6 PARP / cleaved PARP / Akt / caspase 3 / Cleaved caspase 3 pROS1 / ROS1 / pSTAT3 / STAT3 p-EGFR Tyr1068 / EGFR / p-HER3 Tyr1222 / HER3 / p-IGF-1R Tyr1135 / IGF-1R
S2762-WB1
25228534
Growth inhibition assay Cell viability
S2762-viability1
25228534

임상시험 정보 (Clinical Trial Information)

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

NCT 번호 모집 조건 스폰서/협력자 시작일 단계
NCT05987956 Not yet recruiting
Non-small Cell Lung Cancer
Han Xu M.D. Ph.D. FAPCR Sponsor-Investigator IRB Chair|Medicine Invention Design Inc
 March 8 2024 Phase 2|Phase 3
NCT05987644 Recruiting
Lung Cancer|NSCLC|Brain Metastases
Joshua Palmer|Genentech Inc.|Hoosier Cancer Research Network
 March 7 2024 Phase 1|Phase 2
NCT05710133 Enrolling by invitation
NSCLC
The Netherlands Cancer Institute
 February 1 2024 Not Applicable
NCT05770037 Recruiting
Solid Tumor|Haematological Malignancy|Malignant Neoplasm|Lymphoproliferative Disorders|Neoplasms by Histologic Type|Neoplasms by Site|Cancer|Anaplastic Large Cell Lymphoma|Lymphoma|Renal Cell Carcinoma|Neuroblastoma
Cancer Research UK|University of Manchester|University of Birmingham|Royal Marsden NHS Foundation Trust|Hoffmann-La Roche
 December 18 2023 Phase 2|Phase 3
NCT05525338 Recruiting
Drug Monitoring|Carcinoma Non-Small-Cell Lung|Lung Cancer|Anaplastic Lymphoma Kinase Gene Mutation|Anaplastic Lymphoma Kinase Gene Translocation
University Medical Center Groningen|Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)|Erasmus Medical Center|Maastricht University Medical Center|Radboud University Medical Center|The Netherlands Cancer Institute|Leiden University Medical Center
 March 23 2022 Phase 4
NCT04774718 Recruiting
ALK Fusion-positive Solid or CNS Tumors
Hoffmann-La Roche
 September 14 2021 Phase 1|Phase 2