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. Author manuscript; available in PMC: 2022 Dec 1.
Published in final edited form as: Oncogene. 2022 May 7;41(24):3328–3340. doi: 10.1038/s41388-022-02340-8

Fig. 6. Compared to its non-PROTAC analogues (MS40N1 and MS40N2) and a matched WDR5-selective PROTAC (MS169), the WDR5 and IKZF dual degrader MS40 more effectively suppresses the growth of MLL-r acute leukemia cells in vitro.

Fig. 6

A Chemical structure of MS40N2, a MS40 analogue that can bind CRBN but not WDR5. B Immunoblotting for WDR5 and tubulin in MV4;11 cells, treated with the indicated concentrations of MS40N2 for 18 h. C Immunoblotting for WDR5, neo-substrates and tubulin post-treatment of MV4;11 cells with DMSO or 0.5 μM of MS40, MS40N1, MS40N2, or OICR-9429 for 18 h. D Chemical structure of the VHL-based WDR5 PROTAC MS169, which can degrade WDR5 but not the IMiDs:CRBN neo-substrates. E Immunoblotting for WDR5, IMiDs:CRBN’s neo-substrates and tubulin in MV4;11 cells, treated with DMSO, or the indicated concentration of MS40 (0.1 μM and 0.5 μM), MS169 (0.1 μM and 0.5 μM), pomalidomide (0.5 μM), pomalidomide plus OICR-9429 (0.5 μM, 1:1 molar ratio), or MS169 plus pomalidomide (0.5 μM, 1:1 molar ratio) for 18 h. F–J Measurement of growth inhibition effect (y-axis) after a 9-day treatment with the indicated concentration (x-axis) of MS40, MS40N1, or MS40N2, compared with DMSO, in human leukemia lines, MV4;11 F, EOL1 G, RS4;11 H and K562 J. Y-axis, presented in the mean ± SE, shows the proliferation of cells treated with compound for 9 days after normalization to that of DMSO-treated cells (n = 3 independent experiments). I Summary of GI50 values of M40, MS40N1 and MS40N2 (after a 9-day treatment) in the tested human leukemia cell lines. K–M Measurement of the growth-inhibitory effect by MS40, MS40N2, MS169, or MS40N2 plus MS169 (1:1 molar ratio) in MV4;11 K, EOL1 L, and RS4;11 M cells. Y-axis, presented in the mean ± SE, shows the proliferation of cells treated with 0.2 μM or 0.5 μM of compound for the indicated time (x-axis) after normalization to that of DMSO-treated cells (n = 3 independent experiments).