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 Zn 2+ 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 A-mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC 50 of 0.045 Mmol/L in the screening biochemical assay and an EC 50 of 0.025 Mmol/L in HeLa cell -based assays that monitor histone H3 acetylation. KD5170 also exhibits broad spectrum classe

In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Comment in Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016] In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016] US oncologists call for government regulation to curb drug price rises. [BMJ. 2015

2-Chlorodeoxyadenosine to Treat Refractory Histiocytosis X

To the Editor: Treatment of histiocytosis X is palliative at best. It includes corticosteroids, alkylating agents, antimetabolites, vinca alkaloids, and irradiation 1 . Since 2-chlorodeoxyadenosine, a purine substrate analogue active against lymphoid cancers, 2 is toxic to monocytes in vitro, 3 and since tissue histiocytes are derived from circulating monocytes as they move from the intravascular space to soft tissues, we administered 2-chlorodeoxyadenosine to a patient with histiocytosis X. A 33-year-old woman had presented at the age of 15 years with polyuria and polydipsia due to diabetes insipidus. Two years later vesiculopustular lesions developed on her gingiva, scalp, and vagina that were histologically . .