Phosphoglycerate dehydrogenase (PHGDH) is a key enzyme that catalyzes serine biosynthesis and is involved in metabolic reprogramming in cancer. PKUMDL-WQ-2101 is a selective allosteric inhibitor of PHGDH with an IC50 value of 34.8±3.6μM (max inhibition = 67%). Compared to wide-type PKUMDL-WQ-2101, the PHGDH-inhibiting activities were markedly reduced for mutants R134A (IC50 = 141±4μM, max inhibition = 49%) and K57AT59A (IC50 = 128±10μM, max inhibition = 47%). The antitumor activities of PKUMDL-WQ-2101 in two PHGDH amplified breast cancer cell lines (MDA-MB-468 and HCC70) were 7.70μM and 10.8μM, respectively. The IC50 values of PKUMDL-WQ-2101 for the GFP KO cells was 37.3μM. The inhibition of PHGDH by PKUMDL-WQ-2101 (37μM) decreased de novo serine synthesis and metabolism downstream of the serine synthesis pathway in SKOV3 GFP KO cells. PKUMDL-WQ-2101 treatment at a dose of 20mg/kg/day inhibited the growth of MDA-MB-468 xenografts compared with vehicle-treated mice after 30 days of drug delivery[1].
作用机制
PKUMDL-WQ-2101 is a selective allosteric inhibitor of PHGDH. It inhibits PHGDH activity mainly by forming hydrogen-bond networks with site I[1].
搜索
