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Proteolysis targeting chimeric molecules in MM
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Figure 3. ARV 825 rapidly degrades BRD 2 and BRD 4 in KMS11 and KMS28BM multiple myeloma (MM) cells. (A) Immunoblotting of BRD 2, BRD 3 and BRD 4 in KMS11 and KMS28BM cells, cultured for different times with ARV 825: 10 nM (KMS11) and 100 nM (KMS28BM). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH): internal control. (B) Levels of BRD 4 and MYC mRNA expression (left, top and bottom) and protein expression (right) using wild-type KMS11, KMS28BM and their respective cells over-expressing CRBN, cultured with either 10 nM (KMS11) or 100 nM (KMS28BM) of ARV 825 for 4 h. GAPDH: internal control. (C) Protein expression of IKZF 1/3 (Ikaros/Aiolos), BRD 4 and MYC after treatment with ARV 825 (10 nM, KMS11; 100 nM, KMS28BM), MZ1 (100 nM, KMS11; 70 nM, KMS28BM), or combinations of the two PROTAC with either 10 μM pomalidomide (POM) or 5 nM bortezomib (BORT) for 12 h and examined by immunoblotting (GAPDH: internal control). (D) Combination Index plot of ARV 825 with either bortezomib or pomalidomide on KMS11 cells.
haematologica | 2019; 104(6)
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