Drawing upon considerable experience in metalloenzyme inhibitor therapeutics, Karus has designed and developed a novel class of highly-potent and selective inhibitors of HDAC6; KA2507 is the company’s second clinical agent.
HDAC6 is principally a non-histone protein deacetylase, regulating the acetylation status of tubulin and other substrates that play an important role in oncogenesis. HDAC6 is structurally-, expressionally-, and functionally-distinctive within the HDAC superfamily. It is an important drug target in cancer, courtesy of its overexpression in solid tumors, its regulation of tumor cell motility and its role in apoptosis. HDAC6 activity has also been reported to be essential in specific mutant-harboring cancers, and a key role for HDAC6 in tumor immunology has emerged.
Selective HDAC6 inhibition promotes cancer cell apoptosis through the inhibition of aggresome formation. Inhibition of HDAC6 also confers a cancer immunotherapeutic response by regulating immune checkpoint markers within the tumor microenvironment, including downregulation of tumor cell-expression of programmed death ligand 1 (PD-L1); PD-L1 expression is positively correlated with T-cell exhaustion and tumor aggressiveness. As a consequence, KA2507 has significant potential in solid and hematological cancer therapy by targeting tumor cell drivers through its selective inhibition of HDAC6 and its combined direct anti-tumor and tumor immunotherapeutic activity.
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