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.

PROTAC EML4-ALK Degrader-2 (Compound Pro-BA), administered at concentrations ranging from 0 to 1 μM for up to 24 hours, effectively and selectively reduces EML4-ALK levels. It significantly inhibits cell growth in H3122 (DC 50 = 74 nM), BaF3-EML4-ALK (DC 50 = 125 nM), and neuroblastoma SK-N-BE(2) cells (DC 50 = 2.1 μM). At 500 nM for 24 hours, PROTAC EML4-ALK Degrader-2 markedly induces apoptosis in H3122 cells and facilitates EML4-ALK degradation through the ubiquitin-proteasome pathway.

Administered to female nude mice with H3122 xenograft tumors, PROTAC EML4-ALK Degrader-2 (Compound Pro-BA) at 10 mg/kg through intraperitoneal injection every other day for a total of 8 doses significantly reduces EML4-ALK levels and impedes tumor progression. At 25 mg/kg, given orally every two days for 8 doses, it decreases EML4-ALK levels and suppresses tumor growth while demonstrating low toxicity.