Histone deacetylase inhibitors from microorganisms: the Astellas experience.
Histone deacetylase (HDAC) inhibitors, such as trichostatin A and trapoxin, which were first found in microorganisms, potently and selectively inhibit HDAC enzymes. They have made a strong contribution to research on HDACs, chromatin control, abnormal epigenetic control in various diseases and the significance of acetylation in posttranslational modification. Recently, HDAC inhibitors have been focused on as potential drugs for the treatment of several diseases, including cancer, although trichostatin A and trapoxin show no effects in animal models because of their metabolic instability in vivo. Chemical modification has been conducted in order to overcome this drawback. We discovered the microbial metabolites FK228 (also known as FR901228, romidepsin, depsipeptide, NSC-630176 and NSC-630176D) and YM753 (spiruchostatin A). Both compounds have bicyclic structures and represent a novel structural class of HDAC inhibitor. The enzyme and tumor cell growth inhibitory activities of FK228 were found to be very potent. It also showed potent HDAC inhibitory activity in vivo. FK228 is the first potent HDAC inhibitor to undergo clinical development as a potential treatment for solid and hematological cancers. Due to its dramatic effect in patients with refractory cutaneous T-cell lymphoma (CTCL), in October 2004 the US Food & Drug Administration (FDA) granted fast-track status to FK228 as monotherapy for the treatment of CTCL in patients who have relapsed following, or become refractory to, another systemic therapy. Thus HDAC inhibitors such as FK228 and YM753 have potential as tools for life science studies and also as therapeutic agents for various intractable diseases.
Masuoka
Yuhta
Y
Fermentation Research Labs, Drug Discovery Research, Astellas Pharma Inc., 2-3, Tokodai 5-chome, Tsukuba-shi, Ibaraki 300-2698, Japan. yuhta.masuoka@jp.astellas.com
Shindoh
Nobuaki
N
Inamura
Noriaki
N
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D001419:Bacteria / Q000737:chemistry*; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000494:pharmacology; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001688:Biological Products; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; C485419:spiruchostatin A; C087123:romidepsin; D051548:Histone Acetyltransferases