Figure 1
Figure 1. A subset of human myeloma cell lines are readily killed when BCL2 or BCLXL is inhibited with small molecules. (A) Selectivity of well-validated BH3 mimetic compounds for the prosurvival BCL2 proteins. Of the 6 human prosurvival BCL2 proteins, ABT-737 selectively targets BCL2, BCLXL and BCLW.23,24 ABT-263 (navitoclax) is a clinical candidate compound in the same chemical class as ABT-737, and has identical target selectivity.51 The BCL2 selective inhibitor ABT-199 (venetoclax) was developed by modifying ABT-263 such that its affinity for BCLXL and BCLW is reduced.17 Although ABT-737, ABT-263, and ABT-199 are related in their chemical structures, the BCLXL-selective inhibitors A-1155463 and A-1331852 (referred to as A5463 and A1852) belong to a structurally distinct class.20,25 (B) Sensitivity of diverse human myeloma cell lines to the BH3 mimetics. The sensitivity of the 25 myeloma cell lines (details provided in supplemental Table 1) to ABT-737, ABT-199, or A5463 was determined after culturing in 0 to 10 μM of the indicated compound for 48 hours. Cell viability was determined using the CellTiter-Glo assay. IC50 values were calculated using data from 3 independent experiments (eg, in supplemental Figure 1). A discrete heat map representation of the mean IC50s is shown in this panel (actual values are shown in supplemental Table 4): red represents potent killing (IC50 < 0.1 μM), whereas blue indicates resistance (IC50 > 5 μM). (C) Sensitivity of the multiple myeloma cell lines to the selective inhibition of BCL2 or BCLXL. Venn diagram summarizing the sensitivity of the cell lines tested to ABT-737, ABT-199, or A5463. Five lines (KMS-12-BM, KMS-12-PE, KMS-28-BM, KMS-18, and WL-2) are highly sensitive (arbitrarily defined as IC50 < 0.5 μM) to ABT-737, and in agreement with previous studies, the same lines are also very responsive to the BCL2-selective inhibitor ABT-199.11,12 The selective inhibition of BCLXL with A5463 is efficacious in a subset of 5 cell lines: 4 (KMS-34, RPMI-8226, MM1R, MM1S) are distinct from the ABT-737/ABT-199 sensitive ones.

A subset of human myeloma cell lines are readily killed when BCL2 or BCLXL is inhibited with small molecules. (A) Selectivity of well-validated BH3 mimetic compounds for the prosurvival BCL2 proteins. Of the 6 human prosurvival BCL2 proteins, ABT-737 selectively targets BCL2, BCLXL and BCLW.23,24  ABT-263 (navitoclax) is a clinical candidate compound in the same chemical class as ABT-737, and has identical target selectivity.51  The BCL2 selective inhibitor ABT-199 (venetoclax) was developed by modifying ABT-263 such that its affinity for BCLXL and BCLW is reduced.17  Although ABT-737, ABT-263, and ABT-199 are related in their chemical structures, the BCLXL-selective inhibitors A-1155463 and A-1331852 (referred to as A5463 and A1852) belong to a structurally distinct class.20,25  (B) Sensitivity of diverse human myeloma cell lines to the BH3 mimetics. The sensitivity of the 25 myeloma cell lines (details provided in supplemental Table 1) to ABT-737, ABT-199, or A5463 was determined after culturing in 0 to 10 μM of the indicated compound for 48 hours. Cell viability was determined using the CellTiter-Glo assay. IC50 values were calculated using data from 3 independent experiments (eg, in supplemental Figure 1). A discrete heat map representation of the mean IC50s is shown in this panel (actual values are shown in supplemental Table 4): red represents potent killing (IC50 < 0.1 μM), whereas blue indicates resistance (IC50 > 5 μM). (C) Sensitivity of the multiple myeloma cell lines to the selective inhibition of BCL2 or BCLXL. Venn diagram summarizing the sensitivity of the cell lines tested to ABT-737, ABT-199, or A5463. Five lines (KMS-12-BM, KMS-12-PE, KMS-28-BM, KMS-18, and WL-2) are highly sensitive (arbitrarily defined as IC50 < 0.5 μM) to ABT-737, and in agreement with previous studies, the same lines are also very responsive to the BCL2-selective inhibitor ABT-199.11,12  The selective inhibition of BCLXL with A5463 is efficacious in a subset of 5 cell lines: 4 (KMS-34, RPMI-8226, MM1R, MM1S) are distinct from the ABT-737/ABT-199 sensitive ones.

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