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S.L. Lim et al.
Degradation of IKZF 1/3 after exposure to ARV 825
The effect of ARV 825 on IKZF 1/3 degradation was examined using KMS11 and KMS28BM cells [12 h ARV 825 (10 nM, KMS11; 100 nM, KMS28BM), MZ1 (100 nM, KMS11; 70 nM, KMS28BM), pomalidomide (10 μM), bortezomib (5 nM) and combination of PROTAC with either pomalidomide and bortezomib] ARV 825, but not MZ1, degraded IKZF 1/3 (Ikaros/Aiolos), although the degradation was not as significant as was pomalidomide (10 μM) alone. In contrast, BRD 4 was prominently degraded by both PROTAC (Figure 3C).
Bortezomib and pomalidomide antagonized the activity of ARV 825
Pomalidomide reversed the BRD 4 degradation induced by ARV 825, but not by MZ1 (Figure 3C). Pomalidomide was antagonistic to ARV 825 (Figure 3D). Pomalidomide competed with ARV 825 for the binding to CRBN; but, as expected, MZ1 activity was not influenced by pomalido- mide. In contrast, the proteasome inhibitor (bortezomib) antagonized the ability of PROTAC to degrade BRD 4 (Figure 3C and D), indicating the need for an intact protea- some function for PROTAC action. These findings are consistent with a previous study by Zhang et al.13
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P=0.005
Figure 8. ARV 825 inhibits multiple myeloma (MM) samples in vivo. (A) Whole-body bioluminescence images of SCID-beige mice after intravenous injec- tion with KMS11LUC cells (14 days) followed by treat- ment with ARV 825 (5 mg/kg intraperitoneally daily for 28 days) versus vehicle control. (B) Tumor burden as measured by bioluminescence in SCID-beige mice after intravenous injection with KMS11LUC cells (graphic display). Data represent Mean±Standard Deviation (n=9 per group). (C) Survival curves (Kaplan-Meier) of immunodeficient mice who received human MM. The mice who received ARV 825 statistically lived longer (log-rank test, P<0.001).
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haematologica | 2019; 104(6)