WZH-17-002 is a potent, selective ALK PROTAC degrader with DC50 of 25 nM both in H3122 and DFCI076 cells.
WZH-17-002 exhibits anti-proliferative activitiy with IC50 of 17.2 and 15.0 nM against EML4-ALK-G1202R/L1196M and EML4-ALK-L1196M/D1203N Ba/F3 cells respectively.
WZH-17-002 selectively inhibits three NSCLC with ALK rearrangements, DFCI076, H3122 and H2228, with IC50 values of 8.6 nM, 4.5 nM and 58.6 nM, respectively.
WZH-17-002 also exhibits moderate activity against EGFR-driven NSCLC such as PC9 with an IC50 of 179.4 nM.
WZH-17-002 effectively reduces ALK protein levels in H2228 cells with ALK-rearrangement at a low dose of 5 nM, WZH-17-002 also markedly reduces the total ALK protein and phosphorylation levels in Ba/F3 cells expressing EML4-ALK compound mutations such as G1202R/L1196M and I1171S/G1269A.
WZH-17-002 degrades ALK through the proteasome mediated pathway.
WZH-17-002 suppresses the emergence of drug resistance in ALK-fusion NSCLC.
WZH-17-002 (10 mpk or 20 mpk, i.v. injection) exhibits in vivo efficacy in EML4-ALK G1202R/L1196 M Ba/F3 xenograft mouse models.