MS4078 is an anaplastic lymphoma kinase (ALK) PROTAC (degrader) based on Cereblon ligand, with a Kd of 19 nM for binding affinity to ALK[1].
MS4078 effectively inhibits cancer cell proliferation. MS4078 (10-3, 10-2.5, 10-2, 10-1.5, 10-1, 10-0.5, 1 μM; 3 days) concentration-dependently inhibits proliferation of SU-DHL-1 cells with an IC50 of 33±1 nM. In comparison with SU-DHL-1 cells, the proliferation of NCI-H2228 cells is less sensitive to MS4078(10-2, 10-1.5, 10-1, 10-0.5, 1, 100.5 μM; 3 days)[1].MS4078 potently reduces the ALK fusion protein levels and inhibits the ALK auto-phosphorylation and down-steam STAT3 phosphorylation in both SU-DHL-1 and NCI-H2228 cells in a concentration-dependent manner. In SU-DHL-1 cells, MS4078 reduces the NPM-ALK protein levels with impressive DC50 (50% degradation) value of 11±2 nM after 16-hour treatment. Over 90% of inhibition of both ALK Y1507 and STAT3 Y705 phosphorylation is achieved at the 100 nM concentration. In NCI-H2228 cells, MS4078 reduces the EML4-ALK protein levels with similar DC50 value of 59 ± 16 nM after 16-hour treatment. At the 100 nM concentration, NCI-H2228 cells reduces more than 90% of EML4-ALK protein levels[1].
[1]. Zhang C, et al. Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK). Eur J Med Chem. 2018 May 10;151:304-314.