MS4077

MS4077 is an anaplastic lymphoma kinase (ALK) PROTAC (degrader) with a Kd of 37 nM for binding affinity to ALK[1].

Research Areas >> Cancer

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> ALK

Signaling Pathways >> PROTAC >> PROTAC

Kd: 37±4nM (ALK)[1] PROTAC[1]

MS4077 effectively inhibits cancer cell proliferation. MS4077 (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 46 ± 4 nM. In comparison with SU-DHL-1 cells, the proliferation of NCI-H2228 cells is less sensitive to MS4077(10-2, 10-1.5, 10-1, 10-0.5, 1, 100.5 μM; 3 days)[1]. MS4077 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, MS4077 reduces the NPM-ALK protein levels with impressive DC50 (50% degradation) value of 3±1 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, MS4077 reduces the EML4-ALK protein levels with similar DC50 value of 34±9 nM after 16-hour treatment. At the 100 nM concentration, NCI-H2228 cells reduces more than 90% of EML4-ALK protein levels[1]. Cell Viability Assay[1] Cell Line: SU-DHL-1 and NCI-H2228 cells Concentration: 10-3, 10-2.5, 10-2,10-1.5, 10-1, 10-0.5, and 1 μM for SU-DHL-1  cells; 10-2, 10-1.5, 10-1, 10-0.5, 1, 100.5 μM for NCI-H2228 cells Incubation Time: 3 days Result: Inhibited proliferation of SU-DHL-1 cells (IC50=46 ± 4 nM). Less sensitive to the proliferation of NCI-H2228 cells than SU-DHL-1 cells. Western Blot Analysis[1] Cell Line: SU-DHL-1 and NCI-H2228 cells Concentration: 1, 3, 10, 30, and 100 μM for SU-DHL-1 cells; 3, 10, 30, 60, and 100 μM for NCI-H2228 cells Incubation Time: 16 hours Result: Reduced the NPM-ALK protein levels with impressive DC50 of  3 ± 1 nM in SU-DHL-1 cells. Reduced the EML4-ALK protein levels with similar DC50 of 34 ± 9 nM in NCI-H2228 cells.

[1]. Zhang C, et al. Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK). Eur J Med Chem. 2018 May 10;151:304-314.