MS4078

MS4078 is a ALK PROTAC degrader with a DC₅₀ of 11 nM in SU-DHL-1 cells and a DC₅₀ of 59 nM in NCI-H2228 cells, and its K_d value for ALK binding is 19 nM. MS4078 induces ALK degradation via the ubiquitin-proteasome pathway by recruiting cereblon, and inhibits the phosphorylation of ALK and STAT3, thereby suppressing cancer cell proliferation. MS4078 is applicable for the research of non-small cell lung cancer and anaplastic large cell non-Hodgkin's lymphoma^[1][2][3]. IC50 & Target:Kd: 19±3 nM (ALK)^[1]
PROTAC^[1] In Vitro:MS4078 (compound 6) binds to DNA-tagged ALK protein with high affinity, with a K_d value of 19 nM^[1].
MS4078 (1-100 nM; 16 h) potently degrades the NPM-ALK fusion protein in a concentration-dependent manner, with a DC₅₀ of 11 nM, and inhibits the downstream ALK/STAT3 signaling pathway after 16 hours of treatment in SU-DHL-1 cells^[1].
MS4078 (30 nM; 2-24 h) degrades the NPM-ALK fusion protein and inhibits the downstream ALK/STAT3 signaling pathway in SU-DHL-1 cells in a time-dependent manner. At a concentration of 30 nM, its degradation effect peaks at 16 h and persists for at least 24 h^[1].
MS4078 (100 nM; 6 h)-induced degradation of the NPM-ALK fusion protein in SU-DHL-1 cells is mediated by a CRBN- and proteasome-dependent mechanism^[1].
MS4078 (100 nM; 2 h)-induced degradation of the NPM-ALK fusion protein and the inhibition of downstream signaling pathways in SU-DHL-1 cells are reversible, and these effects diminish 8 h after washout^[1].
MS4078 (3-100 nM; 16 h) potently degrades the EML4-ALK fusion protein in a concentration-dependent manner, with a DC₅₀ of 59 nM, and inhibits ALK autophosphorylation in NCI-H2228 cells after 16 hours of treatment^[1].
MS4078 (60 nM; 2-24 h) degrades the EML4-ALK fusion protein and inhibits the downstream ALK/STAT3 signaling pathway in a time-dependent manner in NCI-H2228 cells. At a concentration of 60 nM, significant degradation is observed at 8 h, peak degradation occurs at 16 h, and the effect persists for at least 24 h^[1].
MS4078 (administered for 3 consecutive days) potently inhibits the proliferation of SU-DHL-1 cells, with an IC₅₀ of 33 nM after 3 days of treatment^[1].
MS4078 binds potently to ALK (K_d = 19 nM), degrades ALK fusion proteins in SU-DHL-1 (DC₅₀ =11 nM) and NCI-H2228 (DC₅₀ = 59 nM) cells, and inhibits the proliferation of SU-DHL-1 cells (IC₅₀ = 33 nM)^[3]. In Vivo:MS4078 (compound 6) (50 mg/kg; i.p.; single dose) achieves good plasma exposure in male Swiss albino mice following a single 50 mg/kg intraperitoneal injection, with concentrations maintained above its in vitro antiproliferative IC₅₀ for at least 12 h^[1].
MS4078 (0.5-10 mg/kg; intravenous, oral; single administration) exhibits moderate in vivo clearance in female CD-1 mice when administered intravenously in a vehicle containing Kolliphor. When administered orally as a Kolliphor-containing solution and an SDD formulation, respectively, the oral bioavailability in mice is low, at 3.5% and 1.3%^[2].
MS4078 (50 mg/kg; single dose), an ALK-targeting CRBN-recruiting PROTAC, exhibits favorable in vivo pharmacokinetic properties with excellent plasma exposure and tolerability in mice^[3].