title: KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo.
abstract: Histone deacetylase (HDAC) inhibitors have garnered significant attention as cancer drugs. These therapeutic agents have recently been clinically validated with the market approval of vorinostat (SAHA, Zolinza) for treatment of cutaneous T-cell lymphoma. Like vorinostat, most of the small-molecule HDAC inhibitors in clinical development are hydroxamic acids, whose inhibitory activity stems from their ability to coordinate the catalytic Zn2+ in the active site of HDACs. We sought to identify novel, nonhydroxamate-based HDAC inhibitors with potentially distinct pharmaceutical properties via an ultra-high throughput small molecule biochemical screen against the HDAC activity in a HeLa cell nuclear extract. An alpha-mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC50 of 0.045 micromol/L in the screening biochemical assay and an EC50 of 0.025 micromol/L in HeLa cell-based assays that monitor histone H3 acetylation. KD5170 also exhibits broad spectrum classes I and II HDAC inhibition in assays using purified recombinant human isoforms. KD5170 shows significant antiproliferative activity against a variety of human tumor cell lines, including the NCI-60 panel. Significant tumor growth inhibition was observed after p.o. dosing in human HCT-116 (colorectal cancer), NCI-H460 (non-small cell lung carcinoma), and PC-3 (prostate cancer) s.c. xenografts in nude mice. In addition, a significant increase in antitumor activity and time to end-point occurred when KD5170 was combined with docetaxel in xenografts of the PC-3 prostate cancer cell line. The biological and pharmaceutical profile of KD5170 supports its continued preclinical and clinical development as a broad spectrum anticancer agent.
authors.affiliation: Kalypsys, Inc., 10420 Wateridge Circle, San Diego, CA 92121, USA.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hassig
authors.forename: Kent T
authors.initials: KT
authors.lastname: Symons
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.forename: Phan-Manh
authors.initials: PM
authors.lastname: Nguyen
authors.forename: Tami
authors.initials: T
authors.lastname: Annable
authors.forename: Paul L
authors.initials: PL
authors.lastname: Wash
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Payne
authors.forename: David A
authors.initials: DA
authors.lastname: Jenkins
authors.forename: Céline
authors.initials: C
authors.lastname: Bonnefous
authors.forename: Carol
authors.initials: C
authors.lastname: Trotter
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: John V
authors.initials: JV
authors.lastname: Anzola
authors.forename: Elena L
authors.initials: EL
authors.lastname: Milkova
authors.forename: Timothy Z
authors.initials: TZ
authors.lastname: Hoffman
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Dozier
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Wiley
authors.forename: Alan
authors.initials: A
authors.lastname: Saven
authors.forename: James W
authors.initials: JW
authors.lastname: Malecha
authors.forename: Robert L
authors.initials: RL
authors.lastname: Davis
authors.forename: Jerry
authors.initials: J
authors.lastname: Muhammad
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Shiau
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Noble
authors.forename: Tadimeti S
authors.initials: TS
authors.lastname: Rao
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Smith
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Hager
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011725:Pyridines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C530801:KD 5170; D011725:Pyridines; D013449:Sulfonamides