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).

ALK degrader 2 (Compound J26) demonstrates antiproliferative effects in H3122 cells with an IC50 of 25 nM over 72 hours. Within 24 hours, ALK degrader 2 at concentrations ranging from 0.015 to 5 μM degrades EML4-ALK levels in H3122 cells (DC50 = 8 nM) and reduces nucleophosmin (NPM)-ALK protein levels in SU-DHL-1 cells (DC50 = 102 nM). At concentrations between 0.01 and 0.5 μM for 24 hours, it induces significant S phase cell cycle arrest and apoptosis in H3122 cells. Furthermore, ALK degrader 2 at 0.5 μM for 24 hours mediates ALK degradation via the Hsp70 chaperone and the ubiquitin-proteasome pathway, independent of E3 ligases (CRBN, TTC3, ARK2N).

Compound J26 (ALK degrader 2) administered intravenously at 10 mg/kg significantly reduces EML4-ALK protein levels in tumor tissues of female BALB/c nude mice carrying H3122 xenografts 24 hours post-administration, with sustained inhibition up to 72 hours. Furthermore, Compound J26 demonstrates antitumor activity in H3122 xenograft mice when administered at 20 mg/kg orally or 5-10 mg/kg intravenously every other day for 21 days.