Figure 1.
Mezigdomide has enhanced IKAROS degradation and antiproliferative activity in KMT2A-r and NPM1c cell lines. (A) Proliferation (cell counts) relative to dimethyl sulfoxide (DMSO) control in the MOLM-13 cell line treated for 18 days with 100 nM of lenalidomide (LEN), iberdomide (IBER), or mezigdomide (MEZI), (data pooled from 5 independent experiments; n = 15 per data point; data points represent mean ± standard deviation [SD]). Two-way analysis of variance (ANOVA) with Tukey multiple comparisons test: MEZI vs LEN or IBER: P < .005 for all days from 3 to 18; LEN vs IBER: no significant difference at day 3; P < .005 for all days from 6 to 18. (B) Western blot in MOLM-13 cell line treated for 12 hours. (C) Proliferation relative to DMSO in a panel of KMT2A-r and NPM1c AML cell lines treated for 9 days with 8-point dose curves of LEN, IBER, or MEZI. (n ≥ 3 per data point; data points represent mean ± SD; each curve representative of 3 independent experiments). (D) Absolute IC50 at day 9 for panel C (left) and 5 non–KMT2A-r, non-NPM1c myeloid leukemia cell lines (right) assessed by CellTiter-Glo or cell counts. Bolded and italicized values represent cell lines sensitive to drug (absolute IC50 ≤ 1000 nM). Absolute IC50 calculated with data pooled from 3 independent experiments per cell line for proliferation; 2 independent experiments for CellTiter-Glo assays, with each experiment having at least a 5-point dose titration per IMiD/CELMoD. See supplemental Figure 1I-K for 95% confidence intervals. (E) Proliferation relative to DMSO in CD34+-selected human cord blood cells that were KMT2A-AF9 transformed (left) vs untransformed (middle), assessed at day 6. (Left and middle) Data pooled from 3 independent experiments; n = 9 per data point; data points represent mean ± SD. (Right) For the top concentration of each drug tested in the graphs on the left and middle, proliferation relative to DMSO in KMT2A-AF9 transformed vs untransformed human cord blood cells. Statistical comparison with 1-way ANOVA with Tukey multiple comparisons test; ∗∗∗∗P < .0001.

Mezigdomide has enhanced IKAROS degradation and antiproliferative activity in KMT2A-r and NPM1c cell lines. (A) Proliferation (cell counts) relative to dimethyl sulfoxide (DMSO) control in the MOLM-13 cell line treated for 18 days with 100 nM of lenalidomide (LEN), iberdomide (IBER), or mezigdomide (MEZI), (data pooled from 5 independent experiments; n = 15 per data point; data points represent mean ± standard deviation [SD]). Two-way analysis of variance (ANOVA) with Tukey multiple comparisons test: MEZI vs LEN or IBER: P < .005 for all days from 3 to 18; LEN vs IBER: no significant difference at day 3; P < .005 for all days from 6 to 18. (B) Western blot in MOLM-13 cell line treated for 12 hours. (C) Proliferation relative to DMSO in a panel of KMT2A-r and NPM1c AML cell lines treated for 9 days with 8-point dose curves of LEN, IBER, or MEZI. (n ≥ 3 per data point; data points represent mean ± SD; each curve representative of 3 independent experiments). (D) Absolute IC50 at day 9 for panel C (left) and 5 non–KMT2A-r, non-NPM1c myeloid leukemia cell lines (right) assessed by CellTiter-Glo or cell counts. Bolded and italicized values represent cell lines sensitive to drug (absolute IC50 ≤ 1000 nM). Absolute IC50 calculated with data pooled from 3 independent experiments per cell line for proliferation; 2 independent experiments for CellTiter-Glo assays, with each experiment having at least a 5-point dose titration per IMiD/CELMoD. See supplemental Figure 1I-K for 95% confidence intervals. (E) Proliferation relative to DMSO in CD34+-selected human cord blood cells that were KMT2A-AF9 transformed (left) vs untransformed (middle), assessed at day 6. (Left and middle) Data pooled from 3 independent experiments; n = 9 per data point; data points represent mean ± SD. (Right) For the top concentration of each drug tested in the graphs on the left and middle, proliferation relative to DMSO in KMT2A-AF9 transformed vs untransformed human cord blood cells. Statistical comparison with 1-way ANOVA with Tukey multiple comparisons test; ∗∗∗∗P < .0001.

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