Small-Molecule Inhibitors of Human Ldh5

Abstract

The latest findings on the role played by human LDH5 (hLDH5) in the promotion of glycolysis in invasive tumor cells indicates that this enzyme subtype is a promising therapeutic target for invasive cancer. Compounds able to selectively inhibit hLDH5 hold promise for the cure of neoplastic diseases. hLDH5 has so far been a rather unexplored target, since its importance in the promotion of cancer progression has been neglected for decades. This enzyme should also be considered as a challenging target due the high polar character (mostly cationic) of its ligand cavity. Recently, significant progresses have been reached with small-molecule inhibitors of hLDH5 displaying remarkable potencies and selectivities. This review provides an overview of the newly developed hLDH5 inhibitors. The roles of hLDH isoforms will be briefly discussed, and then the inhibitors will be grouped into chemical classes. Furthermore, general pharmacophore features will be emphasized throughout the structural subgroups analyzed.

Synthesis and biological evaluation of non-glucose glycoconjugated N-hydroyxindole class LDH inhibitors as anticancer agents

“…6 Therefore, several recent research efforts have been dedicated to the development of new LDH-A inhibitors with therapeutic potential as anticancer drugs, although problems related to poor cellular activities of these inhibitors have been often reported. 7,8 …”

Expression of lactate dehydrogenase C correlates with poor prognosis in renal cell carcinoma

“…5 LDH family includes three isoenzymes, namely, lactate dehydrogenase A (LDHA), lactate dehydrogenase B (LDHB) and lactate dehydrogenase C (LDHC). LDHA is abundant in skeletal muscle, 6 and LDHB is predominantly expressed in the brain and heart, 7 but LDHC is strictly limited to the testis, which is essential for maintaining glycolysis and producing adenosine triphosphate (ATP) in spermatogenesis. [8][9][10][11][12] In particular, recent researches have showed LDHC is expressed in a broad spectrum of tumours, with frequent appearance in lung cancer, melanoma and breast cancer.…”

Monitoring a ‘metabolic shift’ after surgical resection of oral squamous cell carcinomas by serum lactate dehydrogenase

“…Measured by immunohistochemistry, our previous study demonstrated LDH‐5 expression, which is the most efficient isoenzyme catalyzing the conversion of pyruvate to lactate as an independent prognostic factor for reduced tumor‐specific survival in OSCC . Therefore, focusing on the LDH‐5 isoform (M subunit) is of potential therapeutic interest by targeted therapies ( e.g., small compounds) for oncologists .…”