eml4-alk

EML4-ALK kinase inhibitor 1 (EML4 ALK kinase inhibitor 1) is a potent oral active inhibitor of echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), with an IC50 of 1 nM.

PROTACEML4-ALK Degrader-2 (Pro-BA) is a selective and orally active EML4-ALK PROTAC degrader without a linker, demonstrating a DC50 of 74 nM and a T1/2 of 8 hours in H1322 cells. It relies on the GID4 and proteasome pathways to facilitate the ubiquitination of target proteins, leading to apoptosis. PROTACEML4-ALK Degrader-2 is applicable in cancer research.

Gilteritinib (ASP2215) is a potent inhibitor of FMS-related tyrosine kinase 3 (FLT3) and AXL tyrosine kinase receptors (IC50 = 0.29 nM and <1 nM, respectively). In preclinical studies, gilteritinib demonstrated strong antileukemic and antitumor effects. Gilteritinib is currently in several Phase 3 clinical trials for acute myeloid leukemia.

JH-VIII-157-02 is an inhibitor of ALK and inhibits echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) with IC50s of 2 nM for EML4-ALK G1202R, EML4-ALKwt, EML4-ALK C1156Y, EML4-ALK F1174L, and EML4-ALK F1174L.

MS4078 is an inhibitor and aplastic lymphoma kinase (ALK) PROTAC (degrader) based on Cereblon ligand, with a Kd of 19 nM for binding affinity to ALK.

dALK-3 is a degrader of anaplastic lymphoma kinase (ALK) that effectively induces the degradation of EML4-ALK with a DC50 of 0.182 μM. It exhibits significant antiproliferative activity against H3122 cells and is applicable for tumor research.

DA-0157 is an orally active inhibitor targeting EGFR and ALK, designed to overcome resistance mutations in non-small cell lung cancer (NSCLC). It effectively inhibits the proliferation of Ba/F3-EGFR Del19/T790M/C797S (IC50= 6.9 nM), Ba/F3-EGFR WT (IC50= 0.83 μM), Ba/F3-EML4-ALK-L1196M (IC50= 5.5 nM), and Ba/F3-EML4-ALK (IC50= 7.4 nM). Additionally, DA-0157 inhibits CYP2D6 with an IC50 of 5.26 μM and demonstrates antitumor activity in mouse models.

PROTACALK degrader-1 (compound B1) is a PROTACs-based ALK degrader with a DC50 of 26 nM in H3122 EML4-ALK. It is utilized in creating PROTACALK degrader-2, which boasts excellent bioavailability.

PROTACALK degrader-2 (B1-PEG) is a PROTAC-based ALK degrader with a DC50 of 45 nM in H3122 EML4-ALK DC50 (GSH+). Through PEGylation, PROTACALK degrader-2 can self-assemble into micelles in water, releasing its active form in tumor-specific high-GSH environments.

WZH-17-002 is an ALKPROTAC degrader based on WZH-15-125, with a DC50 of 25 nM. This compound enhances the efficacy against ALK mutations that confer resistance to Lorlatinib. Moreover, WZH-17-002 significantly reduces resistance in ALK fusion non-small cell lung cancer (NSCLC) and inhibits tumor growth in EML4-ALK G1202R/L1196M xenograft mouse models.

ALK degrader 2 is an orally active ALK degrader that reduces EML4-ALK protein levels (DC50= 8 nM) and nucleophosmin (NPM)-ALK protein levels (DC50= 102 nM). It facilitates ALK degradation through the Hsp70 chaperone system and the ubiquitin-proteasome pathway. In H3122 cells, ALK degrader 2 causes significant cell cycle arrest at the S phase and induces apoptosis. Additionally, it demonstrates antitumor activity in mice with H3122 xenograft tumors. ALK degrader 2 is a useful compound in researching non-small cell lung cancer (NSCLC).

Ensartinib (X-396) is a potent and orally active dual ALK/MET inhibitor for the treatment of ALK-positive non-small cell lung cancer (NSCLC).

ALK-IN-9 (compound 40) is a highly effective ALK inhibitor, demonstrating remarkable inhibitory activity against cell proliferation, with IC50 values of <0.2 nM for Ba/F3-EML4-ALK, KM 12 (TPM3-TRKA), and KG-1 cell (OP2-FGFR1).

Trk-IN-7 (compound I-6) is a highly potent TRK inhibitor, with IC50 values of 0.25-10 nM for TRKA, TRKB, and TRKC, respectively. It also shows significant inhibition of EML4-ALK (IC50 <15 nM) and ALK mutations G1202R, C1156Y, R1275Q, F1174L, L1197M, and G1269A (IC50 = 5-50 nM) [1].

CM-118 is a potent and selective dual inhibitor of c-Met and ALK which potently abrogates hepatocyte growth factor (HGF)-induced c-Met phosphorylation and cell migration, as well as phosphorylation of ALK, EML4-ALK, and ALK resistance mutants in transfected cells.

CPD-1224, an orally active derivative that binds cereblon ligands to ALK inhibitors, specifically targets and degrades EML4-ALK oncogenic fusions, including ALK and its mutants L1196M/G1202R.

ALK/EGFR-IN-1 (Compound 8l) is a dual inhibitor targeting both ALK and EGFR, effectively blocking their phosphorylation. It demonstrates potent inhibition of ALK/EGFR mutants with IC50 values of 4.3 nM for EGFR L858R T790M in H1975 cells and 3.6 nM for EML4-ALK in BaF3 cells. This compound may be applicable in the research of non-small cell lung cancer (NSCLC) [1].

ALK/EGFR-IN-2 is a potent dual inhibitor targeting ALK and EGFR, promoting apoptosis and G0/G1 cell cycle arrest in cancer cells. It effectively suppresses proliferation in H1975, PC9, and Baf3-EML4-ALK cancer cell lines, with IC50s of 0.0034, 0.0065, and 0.0018 μM, respectively [1].

ALK/EGFR-IN-3 is a dual ALK and EGFR inhibitor demonstrating potent anti-proliferative effects on various cancer cell lines, including H1975, PC9, and Baf3-EML4-ALK, with IC50 values of 0.1360, 0.0332, and 0.0339 μM [1].

AP-1, a miniaturized proteolysis-targeting chimera (PROTAC) incorporating an anaplastic lymphoma kinase (ALK) ligand connected to (±)-thalidomide via an ultrashort linker, effectively degrades ALK fusion proteins such as NPM-ALK in Karpas-299 cells and EML4-ALK and ALKF1174L in SN-N-SH and NCI H3122 cells, respectively. Concentrations ranging from 10 to 300 nM are sufficient for its action, which is hindered by the proteasome inhibitor MG-132. Demonstrating selectivity, AP-1 exhibits cytotoxicity towards ALK-dependent Karpas-299 cells with an IC50 value of 0.1265 nM, while showing significantly less toxicity to non-ALK-dependent THP-1 cells (IC50 = 2,704 nM). Furthermore, it effectively reduces tumor volume in NCI H3122 mouse xenograft models at doses of 25, 50, and 100 mg/kg.

22-SLF is a PROTAC degrader that operates by FBXO22-dependent degradation of FK506 Binding Protein 12 (FKBP12) with a DC50 of 0.5 µM. Additionally, 22-SLF can degrade other endogenous proteins, such as BRD4 and the EML4-ALK fusion protein (EML4-ALK fusion protein).

SH-E4A-66 is a C2-COUPLr (COvalent Protein Ligators) featuring a carbazole skeleton, which does not include heterogeneous cysteine-reactive warheads such as acrylamide and chloroacetamide. This compound effectively couples with EML4-ALK (EC50=1.5 μM) and inhibits the kinase activity of EML4-ALK (IC50=2.3 µM).

XMU-MP-5 acts as a selective inhibitor of ALK. It inhibits ALK-mutant Ba/F3 cells with an IC50 ranging from 4-50 nM and induces apoptosis in EML4-ALK Ba/F3 cells. Additionally, XMU-MP-5 demonstrates antitumor activity in mice.