Extended Data Fig. 1: MTHFD2 inhibitor DS18561882 is a weak and unselective inhibitor of MTHFD2. | Nature Cancer

Extended Data Fig. 1: MTHFD2 inhibitor DS18561882 is a weak and unselective inhibitor of MTHFD2.

From: Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress

Extended Data Fig. 1: MTHFD2 inhibitor DS18561882 is a weak and unselective inhibitor of MTHFD2.

(a) Depletion of MTHFD2 induces accumulation of DNA damage in early S phase. Confocal analysis of DNA damage (γH2AX) in U2OS cells expressing the FUCCI sensor system following siRNA knock-down of MTHFD2 (24 h) or hydroxyurea (HU) treatment (2 mM, 24 h). Scale bar, 50 μm. Shown is a representative out of three independent experiments; n (cells/treatment) = 335 (siCtrl), 229 (siMTHFD2), 186 (HU). (b) Structure of the small molecule DS18561882. (c) Dose-response curve (DRC) for the biochemical inhibition of hMTHFD2 by DS18561882 assessed using the NAD(P)H-Glo assay. Graph represents pooled results from four independent experiments carried out in duplicate, with average IC50 value reported (n = 4). Data are displayed as means ± SD. (d) DRC for the biochemical inhibition of hMTHFD1 (DC domain) by DS18561882 assessed using the NAD(P)H-Glo assay. Graph represents pooled results from four independent experiments carried out in duplicate, with average IC50 value reported (n = 4). Data are displayed as means ± SD. (e) Cell viability DRC for DS18561882 in HL-60 cells, evaluated after 96 h. Graph represents pooled results from four independent experiments carried out in duplicate, with average EC50 value reported (n = 4). Data are displayed as means ± SD.

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