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.
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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.
KRCA-0008 is a potent, selective ALK inhibitor with IC50 of 12 nM (wt ALK), also is potent against various ALK mutants, including L1196M, F1174L, R1275Q, and C1156Y (IC50=5-75 nM); weakly inhibits IR (IC50=210 nM), inhibits H3122 and BaF3 EML4-ALK L1196M cell proliferation with IC50 of 80 and 68 nM, respectively; demonstrates in vivo efficacy comparable to Crizotinib in xenograft mice model, has drug-like properties without hERG concerns.
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.
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.
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.
BLU-782 is a activin receptor-like kinase-2 (ALK2) inhibitor extracted from patent WO2017181117A1, Compound 876, has an IC50 of <10 nM
A potent, selective ALK inhibitor with IC50 of 1.9 nM; shows high selectivity versus KDR, KIT and MET (IC50>1,400 nM); exhibits anti-proliferative activity against NPM-ALK-positive cellline KARPAS-299 with IC50 of 3 nM; also inhibits mutant ALK F1174L and R1275Q with IC50 of 1 nM and 3.5 nM respectively; orally active.
Brigatinib (AP-26113, AP26113) is a potent, selective, second generation ALK inhibitor with IC50 of 0.62 nM, exhibits about fivefold greater potency in vitro compared with crizotinib; shows high activity against both sensitive and resistant H3122 cells, decreasing cell growth, suppressing ALK phosphorylation, and inducing apoptosis; AP26113 is also active in Ba/F3 cells expressing either native or mutant EML4-ALK with IC50 of 10 and 24 nM, respectively; demonstrates promising activity in crizotinib resistant.
LDN193189 is a potent, selective BMP type I receptor that inhibits BMP4-induced phosphorylation of SMAD1/5/8 with IC50 of 5 nM, displays >200-fold selectivity for BMP signaling over TGF-β signaling (IC50>1,000 nM); efficiently inhibits transcriptional activity of the BMP type I receptors ALK2 and ALK3 (IC50=5 nM and 30 nM, respectively), with weaker effects on activin and the TGF-β type I receptors ALK4, ALK5 and ALK7; also blocks the transcriptional activity induced by either constitutively active ALK2 R206H or ALK2 Q207D mutant proteins, affects BMP-induced osteoblast differentiation, attenuates ectopic ossification in vivo.
A highly potent and selective, orally active ALK inhibitor with IC50 of 1.9 nM; exhibits no-to-weak inhibition against a panel of 259 kinases and only 15 kinases showes >90% inhibition at 1 uM; shows growth inhibition/cytotoxicity of ALCL, NSCLC, and neuroblastoma cells, and displays dose-dependent inhibition of ALK tyrosine phosphorylation in tumor xenografts in mice (30 mg/kg).
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