Jorge Pincay ’20

Phosphoglycerate mutase 1 (PGAM1) is a gene known to promote rapid tumor growth and invasiveness in several cancers, including non-small cell lung cancer (NSCLC). PGAM1 encodes for an enzyme that catalyzes the conversion of 3-phosphoglycerate to 2-phosphoglycerate in the glycolytic pathway,  a compound that coordinates anabolic biosynthesis. In many forms of cancer, including NSCLC, urothelial bladder cancer, and hepatocellular carcinoma, upregulation of PGAM1 is observed; in these cancers, high levels of 2-phosphoglycerate lead to rapid tumor cell growth and division.

Recently, researchers in Shanghai were able to develop the first allosteric inhibitor of PGAM1, with the goal of mitigating the growth,division, and metastasis of cancer cells. This allosteric inhibitor, formally known as HKB99, was created to be an improved version of a previously synthesized inhibitor known as PGMI-004A. In their study, HKB99 was shown to be a more potent inhibitor of PGAM1 compared to PGMI-004A and  was able to inhibit the non-metabolic functions of PGAM1, such as the facilitation of cell migration. 

The effects of HKB99 were tested in four NSCLC cell lines  (PC9, HCC827, H1975, and A549) and one normal lung cell line (16HBE). Treatment of these cell lines with HKB99 resulted in significant reduction in cell proliferation. IC50 values were obtained for both HKB99 and PGMI-004A, and HKB99 was observed to exhibit  8- to 22-fold greater potency compared to PGMI-004A. HKB99 was also shown to have minor potency for the inhibition of non-mutated healthy human lung cells. A scratch-wound-healing assay was performed in order to assess the ability of HKB99 to inhibit cell migration. In this assay, a small lesion is first made on a monolayer of cells; then, the migration of cells during the wound healing process is assessed by measuring wound confluence (%), or cell confluence in the wound region over time. After PC9 cells and HCC827 cells were wounded and  treated with 0.2 µM HKB99, complete cessation of cell migration was observed after 20 hours, suggesting the potent anti-cancer effects of HKB99. 

Additionally, HKB99 was found to resensitize NSCLC cells to the anti-cancer drug erlotinib, which functions as an epidermal growth factor receptor-tyrosine kinase inhibitor. Erlotinib-resistantPC9 cells and HCC827 cells were treated with various concentrations of HKB99 and erlotinib. Treatment of ER-resistant cancer cells by erlotinib and HKB99 together was shown to inhibit cell proliferation by about 70%, similar to the potency observed after treatment of non-ER-resistant cancer cells with erlotinib alone.

This novel allosteric inhibitor, HKB99, has demonstrated immense potential for future cancer therapy, specifically in NSCLC. In addition to these promising results, these findings have shown that effective methods for cancer therapy can target the alteration  and inhibition of biological pathways within the human body.

Reference:

1. Huang et al., A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer. Cell Metabolism 30, 1-13 (2019). doi: 10.1016/j.cmet.2019.09.014
2. Image retrieved from: Huang et al., A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer. Cell Metabolism 30, 1-13 (2019). doi: 10.1016/j.cmet.2019.09.014