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.

PROTACEML4-ALK Degrader-2 is an EML4-ALK PROTAC degrader. It demonstrates potent selective inhibitory activity against ALK with an IC50 of 1.6 nM. PROTACEML4-ALK also shows selectivity for IGF1R, INSR, FLT3, and FGFR2. Both in vitro and in vivo, PROTACEML4-ALK Degrader-2 exhibits anticancer properties. This compound is applicable in research related to non-small cell lung cancer (NSLC), lung cancer, and cervical cancer.

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).

KF-20444 is an orally active ALK inhibitor with the ability to penetrate the blood-brain barrier. It exhibits potent inhibitory effects on ALK fusion proteins (EML4-ALK) and ALK-resistant mutations, including L1196M, G1202R, and F1174L. KF-20444 effectively suppresses the phosphorylation of ALK in cancer cell lines driven by ALK, thereby inhibiting cancer cell proliferation and inducing apoptosis (apoptosis). In mouse models bearing ALK-positive non-small cell lung cancer or neuroblastoma, it demonstrates antitumor efficacy. KF-20444 is applicable for research into ALK-driven malignancies.

ALK degrader 1 is a potent degrader using hydrophobic tagging technology (HyT), relying on the ubiquitin-proteasome system to degrade EML4-ALK with a DC50 of 0.13 μM. It demonstrates superior ALK degradation and antiproliferative effects in ALK-dependent cell lines, with no significant cytotoxicity in ALK fusion-negative cells. The compound induces G0/G1 cell cycle arrest and promotes apoptosis, efficiently degrades ALK proteins, and blocks key downstream signaling pathways such as STAT3. Additionally, ALK degrader 1 effectively induces EML4-ALK degradation in vivo and is suitable for researching ALK-related diseases.

Gly-PEG3-BA is a PROTAC degrader that targets EML4-ALK. It effectively degrades the EML4-ALK protein in H3122 cells (EML4-ALK positive) with a DC50 of 0.50 μM. In H1975 cells (EGFRL858R/T790M double mutant), Gly-PEG3-BA significantly reduces the levels of the EGFR mutant (L858R/T790M) protein, with a DC50 of 20.15 μM. Additionally, Gly-PEG3-BA exhibits strong antiproliferative activity against H3122 cells and H1975 cells, with IC50 values of 0.84 μM and 20.74 μM, respectively. It is useful for research related to non-small cell lung cancer.

Lys-PEG3-BA is a PROTAC degrader targeting EML4-ALK/EGFR, with DC50 values of 1.32 μM for H3122 cells (expressing EML4-ALK fusion protein) and 19.66 μM for H1975 cells (with EGFRL858R/T790M mutations). In vitro studies show that Lys-PEG3-BA can inhibit the proliferation of non-small cell lung cancer cells by modulating the ubiquitin-proteasome system. Lys-PEG3-BA is applicable for research related to non-small cell lung cancer.

PROTACALK degrader-5 (Compound 17) is a potent ALKPROTAC degrader with activities of 27.4 nM against EML4-ALK and 116.5 nM against NPM-ALK. It exhibits strong antiproliferative effects on H3122 and Karpas 299 cell lines and effectively inhibits the phosphorylation of ALK and STAT3. This compound is applicable for studying ALK-driven malignancies, such as human non-small cell lung cancer and anaplastic large cell lymphoma.

Pro-PEG3-BA is a PROTAC degrader targeting EML4-ALK and EGFR, effectively degrading EML4-ALK and EGFR mutants (L858R/T790M) with DC50 values of 0.42 μM and 13.50 μM, respectively. In vitro, it inhibits the proliferation of non-small cell lung cancer cells, inducing cell cycle arrest and apoptosis. Pro-PEG3-BA demonstrates favorable safety characteristics and can reduce EML4-ALK protein expression by modulating the ubiquitin-proteasome system in vivo, making it suitable for research on non-small cell lung cancer.

TRI-611 is a highly selective ALK molecular chaperone degrader that can cross the blood-brain barrier. By binding to the CRBN E3 ligase, it induces the ubiquitination and proteasomal degradation of ALK fusion proteins. TRI-611 efficiently degrades various EML4-ALK fusion proteins, including TKI-resistant mutants, and demonstrates significant antitumor activity in ALK-positive non-small cell lung cancer (NSCLC) models. TRI-611 induces tumor regression in subcutaneous and intracranial xenograft models and is equally effective in models resistant to ALK tyrosine kinase inhibitors (TKIs), making it a valuable tool for research into ALK-driven tumors and resistance mechanisms.

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.