HDAC Inhibitor ProgramHDAC8-Specific Inhibitor Program: PCI-34051
Pharmacyclics' scientists have been at the forefront of research into inhibitors for specific HDAC enzymes beginning with the cloning of the human HDAC8 in 2000 (Buggy et al., Biochem J., 2000). Since then, we were the first to crystallize the protein Close A class of molecules (including enzymes, antibodies, or structural proteins) that are built from amino acid components to perform a wide range of functions in the cell.
ProteinLeukemiaA cancer of the blood or bone marrow and is characterized by an abnormal proliferation (production by multiplication) of blood cells, usually white blood cells (leukocytes). 2008), and the first to discover a novel anti-inflammatory activity of an HDAC8 inhibitor (Balasubramanian et al., in preparation 2009). This has led to a strong intellectual property position, with multiple patents on the gene, protein, a large panel of selective inhibitors, and worldwide recognition of our efforts with seminar and poster presentations at major international conferences.
We have identified multiple clinical applications for this class of drugs:
T-cell lymphoma
PCI-34051 induces growth arrest and apoptosis Close Programmed cell death or suicide that results from interrupted cellular functions. A chemical compound that inhibits histone deacetylases (HDACs) and is used to treat cutaneous T-cell lymphoma.ApoptosisT-CellA group of white blood cells known as lymphocytes that play a central role in cell-mediated immunity.lymphomas and leukemias, while not affecting other hematologic tumors and most solid tumors (Balasubramanian et al., Leukemia. 2008). Thus, PCI-34051 has the potential to offer an improved therapeutic index CloseTherapeutic IndexComparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects.
in these indications over non-selective HDAC inhibitors including vorinostat, CloseVorinostatCutaneousRelating to the skin.T-Cell Lymphoma CloseLymphomaA cancer that is detected in the lymph nodes and ducts as well as in the blood. (CTCL) in 2006 but has been associated with multiple toxic effects.
Pediatric neuroblastoma
HDAC8, unique among the general group of HDAC enzymes, is overexpressed in pediatric neuroblastoma tumors, and a high HDAC8 expression level is strongly associated with a poor prognosis for this disease (Oehme et al., Clin Cancer Res. 2009). HDAC8-specific inhibitors induce growth inhibition and differentiation into non-tumor forms of neuroblastoma cells. Thus, HDAC8-specific inhibitors could prove valuable in treating this disease for which there is no present cure.
Inflammatory disease
We have discovered that PCI-34051 inhibits the secretion of many pro-inflammatory proteins from blood cells (Balasubramanian et al., in preparation 2009). It is particularly effective at modulating the proteins interleukin-1 beta (IL1b) and interleukin-18, both of which are associated with many autoimmune Close An immune response by the body against its own cells or tissues. Affecting the entire body. An inherited inflammatory (autoinflammatory) condition that appears as rash, fevers and chills after exposure to cold. A common chronic, inflammatory disease that affects the skin and joints and is characterized by scaly patches on the skin.AutoimmuneSystemicStills diseaseA type of juvenile rheumatoid arthritis.
(Lequerre et al., Ann.Rheum.Dis. 2008), Familial Cold Syndrome CloseFamilial Cold SyndromeMuckle-Wells SyndromeA rare inherited disease that is characterized by episodic inflammation and fevers that may lead to deafness.(Farasat et al., Arch.Dermatol. 2008). We have also shown that PCI-34051 is effective at reducing IL1b secretion from blood cells of patients with RA and psoriasis ClosePsoriasis