Structural Basis of the Antiproliferative Activity of Largazole, a Depsipeptide Inhibitor of the Histone Deacetylases

Abstract

Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 Å-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with a macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax® recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors.

Romidepsin and the Zinc‐Binding Thiol Family of Natural Product HDAC Inhibitors

“…Largazole is the only natural product among the zinc-binding thiol family of HDAC inhibitors for which X-ray structural information is available for the enzyme-inhibitor complex. A 2.14 Å-resolution (0.214 nm) crystal structure of the HDAC8-largazole thiol complex was solved by Christianson and confirms the Yoshida hypothesis (Figure 2.4) with the thiolate coordinated to the active site zinc and the cap interacting with the rim region of the enzyme [30].…”

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

“…Although crystal structure of the HDAC-FK228 (a cyclic peptide inhibitor) complex has not yet been solved, computer-modeling studies suggest that one of the thiol groups generated by reduction can coordinate to the active site zinc ion (Furumai et al 2002). Recently, a similar inhibitory mechanism was proven by the crystal structure of HDAC8 with hydrolyzed largazole (Cole et al 2011). Largazole has a thioester moiety, which can be hydrolyzed in cells to give an active thiol side chain (Fig.…”

Histone deacetylases: structural determinants of inhibitor selectivity

“…To date, 39 crystal structures of human HDACs (isoforms 1, 2, 3, 4, 7, and 8) and eight for HDAC homologs from bacteria (HDLP and HDAH) have been solved [19,40,[43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] (Tables 2 and 3). …”