生物活性

• 描述TL13-112 is PROTAC selectively targeting on ALK with DC50 values of 10nM and 40nM in H3122 and Karpas 299 cells, respectively, consist of an ALK-binding LDK378 ligand linked to Pomalidomide. TL13-112 exhibited anti-proliferative effect on H3122, Karpas 299, SU-DHL-1, Kelly and Lan5 with 26.4, 9.2, 2.4, 374 and 934nM, respectively, post 72-hour treatment, but with much less potency to SH-SY5Y and CHLA20 cells. The co-treatment with P-gp inhibitor Tariquidar (125nM) could improve the anti-proliferative potency of TL13-112 on Kelly, Lan5, SH-SY5Y and CHLA20 cells. Degrader behavior of TL13-112 may differ from various cell lines. TL13-112 at concentration of 500nM achieved max degradation of ALK in H3122 and Karpas 299 cells at 16h, but with a significant degradation of Aurora A observed. The phosphorylation levels of ALK^Y1604 site and its downstream STAT3^Y705 phosphorylation site were decreased post 6-48h accompanied with the degradation of ALK protein by TL13-112 (250nM) in H3122 and Karpas 299 cells. However, it degraded ALK in Kelly and CHLA20 (co-treated with Tariquidar) cells without significant effect on Aurora A (at concentration<160nM), without significant change of its downstream p-STAT3^Y705 level up to 48h (at concentration of 250nM). TL13-110 is a negative control of TL13-112^[1].