Hypothemycin, a Fungal Polyketide, is a Multikinase Inhibitor

The kinase is an enzyme. And it catalyzes the transfer of a phosphate group from a high-energy donor molecule to a specific target molecule. This process is phosphorylation. In general, the purpose of phosphorylation is to “activate” or “enable” a substrate, increasing its energy so that it can participate in subsequent reactions. Importantly, all kinases require the presence of a divalent metal ion that stabilizes the high-energy bond of the donor molecule and provides the possibility for phosphorylation to occur. Besides, the phosphorylation state of a molecule can affect its activity, reactivity and its ability to bind other molecules. Therefore, kinases are critical in metabolism, cell signalling, protein regulation, cellular transport, secretory processes and many other cellular pathways.

The largest family of kinase is the protein kinases. The human genome contains about 500 protein kinase genes, accounting for about 2% of human genes. The protein kinase selectively modifies other proteins by covalently adding phosphates to them (phosphorylation). Phosphorylation of proteins determines the structure and activity of proteins and affects intracellular signaling processes in order to respond appropriately to external stimuli. Different other kinases act on small molecules (lipids, sugars, amino acids, nucleosides, etc.), either to signal or to prepare them for various biochemical reactions in metabolism.

Hypothemycin is a multikinase inhibitor.

Hypothemycin, an electrophilic polyketide natural product, is a multikinase inhibitor. Specifically, Hypothemycin can inhibit VEGFR2/VEGFR1, MEK1/MEK2, FLT-3, PDGFRβ/PDGFRα, and ERK1/ERK2. Meanwhile, Hypothemycin can covalently inactivate several human kinases bearing a cysteine adjacent to the conserved DXG motif. in vitro, Hypothemycin also shows antiproliferative activity. Hypothemycin inhibits growth of cancer cell lines, such as leukemia cells, melanoma cells, mastocytoma cells, NSCLC cells, and ovarian cells. In vivo, Hypothemycin kills T. brucei in infected mice.

[1]. Gal-Ben-Ari S, et, al. Front Mol Neurosci. 2019 Jan 9;11:480.