Figure 3. In vitro and in vivo efficacy of PHGDH inhibitors.

a, Selective toxicity of NCT-503 towards five cell lines that overexpress PHGDH relative to three cell lines with low PHGDH expression. Data points are the average of three independent biological experiments and error bars represent standard deviations. b, Compound cytotoxicity towards PHGDH-expressing MDA-MB-468 cells correlates with inhibition of M+3 serine production. Each data point represents an EC₅₀ that is the average of three independent experiments and a single IC₅₀ flux experiment comprised of 6 data points. c, NCT-503 reduces the volume of MDA-MB-468 orthotopic xenografts while sparing the growth of MDA-MB-231 xenografts. Data points are the mean of ten animals, and error bars represent standard error of the mean. *, p<0.05, Student’s t-test. d, NCT-503 reduces the weight of MDA-MB-468 xenografts but not the weight of MDA-MB-231 xenografts. Each data point is a single animal, n=10 in each arm. Horizontal bar indicates the mean of ten animals and error bars represent standard error of the mean. *, p<0.05, Student’s t-test. e, NCT-503 increases the fraction of necrosis in MDA-MB-468 orthotopic xenografts but not in MDA-MB-231 orthotopic xenografts. Scale bars, 2 mm. Images are representative of ten animals. Each data point is a single animal, n=10 in each arm. Horizontal bar indicates mean of ten animals and error bars represent standard error of the mean. *, p<0.05, Student’s t-test. f, Following infusion of U-¹³C glucose, NCT-503 reduces the fraction of M+3 serine (normalized to M+3 3-PG) in MDA-MB-468 orthotopic xenografts. Data are the mean of three independent experiments (3 animals in each arm) and error bars represent standard deviations. *, p<0.05, Student’s t-test.