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.

ALK degrader 1 (compound H7) demonstrates antiproliferative effects in ALK-dependent cell lines, with an IC50 of 0.23 μM in H3122 cells and 0.19 μM in Karpas 299 cells. At concentrations of 0.5–5 μM for 24 hours, it effectively degrades EML4-ALK in H3122 cells, achieving over 80% degradation at 0.5 μM, while its activity against NPM-ALK in Karpas 299 cells is relatively weaker, with approximately 70% degradation at 5 μM. With concentrations ranging from 0.1–5 μM for 2–24 hours, ALK degrader 1 acts as a potent EML4-ALK degrader (DC50 = 0.13 μM), featuring rapid and sustained degradation, and effectively inhibits ALK phosphorylation and downstream STAT3 signaling in H3122 cells. Following withdrawal of the compound at 2 μM for 24 hours, the degradation effect on EML4-ALK persists for up to 48 hours. Moreover, at 0.5–2 μM for 24 hours, it effectively hinders mitosis in H3122 cells, inducing G0/G1 phase arrest and apoptosis. Additionally, ALK degrader 1 at 2 μM for 24 hours upregulates ALK mRNA expression, promotes ALK interaction with Hsp70, and its degradation activity can be significantly inhibited by MG-132, suggesting reliance on the ubiquitin-proteasome pathway. It exhibits good selectivity for ALK-negative tumor cells (A549) and normal lung epithelial fibroblasts (HFL-1) at 0.1–1 μM for 72 hours, with no notable side effects, indicating favorable safety.

Administered intravenously at a dose of ALK degrader 1 (20 mg/kg, single injection), this compound effectively degrades the EML4-ALK protein in tumor tissues within the H3122 xenograft mouse model.