NVP-AEW541

NVP-AEW541 (AEW-541, AEW541) is a potent, and selective inhibitor of IGF-1R with IC50 of 86 nM; shows weak activity for closely related InsR (IC50=2.3 uM) ; inhibits IGF-IR autophosphorylation and abrogates IGF-I-mediated survival and colony formation in soft agar; inhibits IGF-IR signaling in tumor xenografts and significantly reduces the growth of IGF-IR-driven fibrosarcomas in vivo; orally bioavailable.Blood Cancer Phase 1 Clinical (In Vitro) :NVP-AEW541 inhibits the in vitro kinase activity of the recombinant IGF-IR kinase domain with an IC50 value of 0.15 μM and to be equipotent against the recombinant InsR kinase domain. NVP-AEW541 is confirmed active toward the IGF-IR kinase (IC50=86 nM) and shown to be selective at the cellular level. Indeed, NVP-AEW541 is found to be 27-fold more potent toward the native IGF-IR, as compared to the structurally related native InsR (IC50=2.3 μM) . NVP-AEW541 suppresses the IGF-I-mediated survival, soft agar and proliferation of MCF-7 cells with IC50 of 0.162 μM, 0.105 μM and 1.64 μM, respectively. (In Vivo) :Oral administration of NVP-AEW541 (20, 30, or 50 mg/kg) results in abrogation of basal and IGF-I-induced receptor, and PKB and MAPK phosphorylation in the NWT-21 tumor xenograft. NVP-AEW541 is administered by oral gavage [50 mg/kg in 0.2 mL of 25 mM L- (+) -tartaric acid] twice a day for 14 consecutive days. The control group is similarly treated with 0.2 mL carrier [25 mM L- (+) -tartaric acid] twice a day. Tumor volume and animal weight are measured thrice a week till the end of the treatment. At that time, animals are sacrificed and tumors are collected and formalin fixed for histologic and immunohistochemical analyses. In both cases, NVP-AEW541 treatment causes tumor shrinkage that reached the statistical significance (P=0.0156 and P=0.0111 for HTLA-230 and SK-N-BE2c, respectively) .