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Anaplastic lymphoma kinase (ALK), also known as CD246, is a receptor tyrosine kinase having a putative transmembrane domain and an extracellular domain. ALK activation is involved in the carcinogenesis process of several human cancers such as anaplastic large cell lymphoma, lung cancer, inflammatory myofibroblastic tumors and neuroblastoma, as a consequence of fusion with other oncogenes (NPM, EML4, TIM, etc) or gene amplification, mutation or protein overexpression.

Specific inhibitors, such as crizotinib, ceritinib, alectinib etc., has demonstrated significant effectiveness in ALK-positive patients, in particular ALK-positive non- small cell lung cancer. The EML4-ALK fusion gene is responsible for approximately 3-5% of non-small-cell lung cancer(NSCLC). The vast majority of cases are adenocarcinomas. Crizotinib is a first-in-class ALK tyrosine kinase inhibitor (TKI), which has proven its superiority over standard platinum-based chemotherapy for the first-line therapy of ALK-rearranged non-small cell lung cancer (NSCLC) patients. Ceritinib and alectinib are approved second-generation ALK TKIs. Several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib, are currently in development.

References:

1. Della Corte CM, et al. Mol Cancer. 2018 Feb 19;17(1):30.

2. Wu W, et al. Cancers (Basel). 2017 Nov 30;9(12). pii: E164.

3. Muller IB, et al. Onco Targets Ther. 2017 Sep 13;10:4535-4541.

4. Karachaliou N, et al. Expert Opin Investig Drugs. 2017 Jun;26(6):713-722.

 

Cat. No. Product Name CAS No. Information
PC-62298

TPX 0005

1802220-02-5

TPX 0005 (Ropotrectinib, Repotrectinib, TPX0005) is a novel ALK/ROS1/TRK inhibitor, effectively inhibits a broad spectrum of mutations including solvent front ALK G1202R, ROS1 G2032R and TRKA G595R mutants; potently inhibits WT ALK (IC50=1.01 nM) and mutant ALKs including ALK G1202R (IC50=1.26 nM) and ALK L1196M (IC50=1.08 nM); is also a potent SRC inhibitor (IC50=5.3 nM); shows low nano-molar activities against CD74-ROS1 G2032R (IC50=8.4 nM), LMNA-TRKA G595R (IC50=0.4 nM),TEL-TRKB G639R (IC50=1.9 nM) and TEL-TRKC G623R (IC50=0.4 nM) in Ba/F3 cell proliferation assays; dramatically causes tumor growth inhibition and tumor regression in xenograft tumor model; demonstrates desired druglike properties and good safety profile.

Solid Tumors

Phase 2 Clinical

PC-45886

Crizotinib hydrochloride

1415560-69-8

Crizotinib (PF-02341066;PF-2341066) is a potent, selective, orally bioavailable, ATP-competitive inhibitor of c-Met catalytic activity with Ki of 4 nM; displays >1,000-fold selective for the VEGFR2 and PDGFRβ RTKs, >250-fold selective for IRK and Lck, and ∼40- to 60-fold selective for Tie2, TrkA, and TrkB; also inhibits ALK (IC50=24 nM), potently inhibits c-Met phosphorylation and c-Met-dependent proliferation, migration, or invasion of human tumor cells in vitro (IC50=5-20 nM); shows antitumor efficacy in tumor models at well-tolerated doses in vivo.

Lung Cancer

Approved

PC-45885

Crizotinib

877399-52-5

Crizotinib (PF-02341066;PF-2341066) is a potent, selective, orally bioavailable, ATP-competitive inhibitor of c-Met catalytic activity with Ki of 4 nM; displays >1,000-fold selective for the VEGFR2 and PDGFRβ RTKs, >250-fold selective for IRK and Lck, and ∼40- to 60-fold selective for Tie2, TrkA, and TrkB; also inhibits ALK (IC50=24 nM), potently inhibits c-Met phosphorylation and c-Met-dependent proliferation, migration, or invasion of human tumor cells in vitro (IC50=5-20 nM); shows antitumor efficacy in tumor models at well-tolerated doses in vivo.

Lung Cancer

Approved

PC-35352

JH-VIII-157-02

1639422-97-1 JH-VIII-157-02 is a potent, orally active, CNS-permeable, second-generation inhibitor of ALK G1202R mutant with IC50 of 2 nM, also shows high potency against a variety of other frequently observed mutants (G1269A, S1206Y, F1174L and C1156Y); inhibits EML4-ALKWT with IC50 of 2 nM, demonstrates inhibition of CSNK2A1 <10 uM, IRAK1 (IC50 =14 nM), IRAK4 with (IC50=465 nM), CLK4 (IC50=14 nM), RET (IC50=3 nM), RET V804L (IC50=13 nM); potently inhibits proliferation of NSCLC H3122 cell line with IC50 of 5 nM.
PC-35262

WY-135

2163060-83-9 WY-135 (WY135) is a novel potent inhibitor of ALK and ROS1 with IC50 of 1.2 and 0.48 nM, respectively; exhibits better enzyme inhibitory activity than ceritinib, demonstrates anti-proliferative effects on Karpas299 and H2228 cells with IC50 of 28 and 164 nM respectively in MTT assay; induces cell cycle arrest at G1 phase in a dose-dependent manner and subsequently progressed into apoptosis, significantly suppressed ALK and its downstream protein expression.
PC-43495

ASP3026

1097917-15-1 ASP3026 is a potent small molecule ALK inhibitor with IC50 of 3.5, 10, 5.4 and 6.8 nM for wt ALK, ALK F1174L, ALK R1275Q and NPM1-ALK, respectively; also potently inhibits Ack, EGFR L858R, FRK and LTK with IC50 of 5-85 nM, inhibits the growth of NCI-H2228 cells with IC50 of 64.8 nM; enhances the antitumor activities of paclitaxel and pemetrexed without affecting body weight in mice model.

Blood Cancer

Phase 1 Discontinued

PC-43330

GSK1838705A

1116235-97-2 GSK1838705A is a potent, specific inhibitor of IGF-IR and insulin receptor (IR) with IC50 of 2.0 and 1.6 nM, also is a potent inhibitor of ALK with IC50 of 0.5 nM; display excellent kinase selectivity on a panel of 224 unique protein kinases with only 7 additional kinases to be inhibited by >50% at 0.3 uM; inhibits a panel of cell lines derived from solid and hematologic tumors with IC50 of 20 nM-8 uM (NCI-H929 IC50=197 nM); causes complete regression of ALK-dependent tumors, retards the growth of human tumor xenografts in vivo with minimal effects on glucose homeostasis.

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