PGMI-004A is an effective inhibitor of phosphoglycerate mutase 1 (IC50: 13.1 μM).

PGAM1:13.1 μM

PGMI-004A inhibits PGAM1 with an IC50 of approximately 13.1 μM and the Kd value of the PGMI-004A-PGAM1 interaction is determined to be 7.2±0.7 μM from the fluorescence-based binding assay. PGMI-004A treatment induces decreased cell proliferation of diverse human cancer and leukemia cells, but not control human dermal fibroblasts (HDF), human foreskin fibroblasts (HFF), human HaCaT keratinocyte cells and human melanocyte PIG1 cells, suggesting minimal non-specific toxicity of PGMI-004A in normal, proliferating human cells. PGMI-004A may allosterically modulate the enzyme activity of PGAM1. The Ki value is determined to be 3.91±2.50 μM using a Dixon plot analysis. The Kd value for protein-ligand interaction is calculated to be 9.4±2.0 μM. PGMI-004A (20 μM) treatment, causes significantly reduced lactate production that is rescued by methyl-2-PG treatment but has no significant effect on intracellular ATP levels. Inhibition of PGAM1 activity by PGMI-004A (20 μM) treatment results in decreased 2-PG and increased 3-PG levels in H1299 cells, which could be rescued by treatment with methyl-2-PG. PGMI-004A (20 μM) treatment results in decreased oxidative PPP flux and NADPH/NADP+ratio, as well as reduced biosynthesis of lipids and RNA, and cell proliferation in H1299 cells [1].

Treatment with PGMI-004A significantly reduces tumor growth and size in mice when compared to those treated with a vehicle control. It effectively inhibits PGAM1 enzyme activity within tumors of nude mice bearing xenografts. The xenograft model is established by injecting H1299 cells into nude mice, and after six days, the mice are segregated into two groups (n=8/group). They are subsequently treated with either PGMI-004A (100mg/kg/day) or a vehicle for 21 days [1].