RESUMEN
Pyruvate kinase converts phosphoenolpyruvate to pyruvate, catalyzing the rate-limiting step of glycolysis. The M1 isoenzyme of pyruvate kinase (PKM1) is found in adult tissues; whereas, PKM2 is a splicesome variant found in embryonic and cancer cells. PKM2 expression in malignant cells is a result of the tumor microenvironment and is responsible for maintaining a glycolytic phenotype. PKM2 has other nonmetabolic functions in malignant cells, including transcriptional coactivation and protein kinase activity. PKM2 activators have antitumor properties by inducing tetramerization of two PKM2 dimers causing PKM2 to function like PKM1. Restoring PKM2 to PKM1-like levels of activity causes reversal of the Warburg effect in cancer cells. PKM2 activators have therapeutic potential in the treatment of cancer and other metabolic diseases.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Proteínas Portadoras/agonistas , Proteínas de la Membrana/agonistas , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Hormonas Tiroideas/agonistas , Animales , Antineoplásicos/uso terapéutico , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Descubrimiento de Drogas , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Terapia Molecular Dirigida , Neoplasias/enzimología , Neoplasias/genética , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Hormonas Tiroideas/genética , Hormonas Tiroideas/metabolismo , Proteínas de Unión a Hormona TiroideRESUMEN
The proto-oncogene proviral integration site for moloney murine leukemia virus (PIM) kinases (PIM-1, PIM-2, and PIM-3) are serine/threonine kinases that are involved in a number of signaling pathways important to cancer cells. PIM kinases act in downstream effector functions as inhibitors of apoptosis and as positive regulators of G1-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, and prostate, gastric, and head and neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma and to assess the role PIM function in disease progression and their potential to serve as molecular targets for therapy. One hundred thirty-seven cases of urothelial carcinoma were included in this study of surgical biopsy and resection specimens. High levels of expression of all three PIM family members were observed in both noninvasive and invasive urothelial carcinomas. The second-generation PIM inhibitor, TP-3654, displays submicromolar activity in pharmacodynamic biomarker modulation, cell proliferation studies, and colony formation assays using the UM-UC-3 bladder cancer cell line. TP-3654 displays favorable human ether-à-go-go-related gene and cytochrome P450 inhibition profiles compared with the first-generation PIM inhibitor, SGI-1776, and exhibits oral bioavailability. In vivo xenograft studies using a bladder cancer cell line show that PIM kinase inhibition can reduce tumor growth, suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas.
