Alpha-mercaptoketone based histone deacetylase inhibitors

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Pharmacology

Background:

• Histone deacetylases (HDACs) are crucial epigenetic regulators implicated in various diseases, including cancer.
• Developing novel non-hydroxamic acid HDAC inhibitors is an active area of research for improved therapeutic agents.
• Targeting HDACs offers a promising strategy for cancer therapy.

Purpose of the Study:

• To identify and optimize novel non-hydroxamic acid inhibitors of histone deacetylase (HDAC).
• To evaluate the in vitro and in vivo efficacy of a lead alpha-mercaptoketone compound as an HDAC inhibitor.

Main Methods:

• High-throughput screening (HTS) to identify initial hits.
• Lead optimization through medicinal chemistry modifications.
• In vitro enzymatic assays to determine inhibitory potency.
• In vivo studies to assess anti-tumor efficacy.

Main Results:

• A novel alpha-mercaptoketone scaffold was identified as a potential HDAC inhibitor.
• Lead optimization yielded potent HDAC inhibitors with nanomolar in vitro activity.
• Compound 19y (KD5150) demonstrated significant inhibition of tumor growth in vivo.

Conclusions:

• Alpha-mercaptoketones represent a promising novel class of non-hydroxamic acid HDAC inhibitors.
• Compound 19y (KD5150) shows therapeutic potential for cancer treatment.
• Further development of these compounds could lead to new anti-cancer drugs.