HDAC8-Selective Inhibitors

Pharmacyclics is also in the forefront of developing HDAC inhibitors that are highly selective for individual isoforms, which may exhibit reduced side effects compared to the pan-HDAC inhibitors, while retaining efficacy in specific subsets of indications where each isoform plays a critical role (Balasubramanian et al 2009).

Pharmacyclics has focused on the HDAC8 isoform as a promising target (Buggy et al., Biochem J., 2000). A series of compounds have been developed with very high selectivity for HDAC8 that includes the lead PCI-34051 (Balasubramanian et al 2008), which was shown to have growth proliferative and apoptosis-inducing activity in T-cell lymphomas and leukemias, but not in other B-cell or myeloid lymphomas or in most solid tumors. There may also be a role for HDAC8 in neural crest development, and these HDAC8-selective inhibitors showed activity against neural-crest derived tumors, including neuroblastoma (Oehme et al 2010). We are currently pursuing preclinical development of these new compounds in various diseases.