HDAC Inhibitors: Unraveling Cancer Cells

Inhibitors of histone deacetylase (HDAC) enzymes have received increasing attention from researchers examining new ways to target cancer cells without harming normal tissue. In the cell nucleus, DNA is present with proteins as part of a tightly compacted complex called chromatin. HDAC enzymes play a role in modifying the structure of chromatin, allowing DNA transcription – a process by which DNA controls cellular activity – to occur. HDAC inhibitor PCI-24781 alters the transcription process in a manner that leads to tumor cell death (apoptosis), and also renders tumors more sensitive to chemotherapeutic drugs.

Pharmacyclics' HDAC Program

Pharmacyclics' lead HDAC inhibitor, PCI-24781, is being evaluated in Phase 1 and 2 clinical trials. The drug inhibits all forms of HDAC enzymes, to target a broad range of cancer types. The Phase 1 trial (Study 0402) is designed to assess the safety and tolerability of an oral formulation of the drug and determine the maximum tolerated dose. Recent clinical studies indicate that PCI-24781 provides drug exposure sufficient to inhibit HDAC enzymes following oral administration at doses that are well tolerated.

A Phase 2 trial (Study 0403) is evaluating PCI-24781 in patients with recurrent lymphoma. This study is designed to assess safety of a novel dosing regimen and efficacy. It is also evaluating a biomarker known as RAD51, found by Pharmacyclics scientists to be overexpressed in certain cancers and may underlie resistance to therapy. This research was published in the Proceedings of the National Academy of Sciences.

Pharmacyclics’ scientists have also developed isoform selective HDAC inhibitors targeting HDAC8, a protein involved in T-cell leukemia that is also critical in immune function.