Selective histone deacetylase 6 (HDAC6) inhibition: an innovative approach targeting aggresome formation and inhibiting PD-L1 expression in cancer

Our lead HDAC6-selective inhibitor, KA2507, has significant therapeutic potential in solid and hematological tumor therapy through its combined pro-apoptotic and immunotherapeutic activity. KA2507 is in late pre-clinical studies at the MD Anderson Cancer Center in Houston.

Drawing on considerable experience in metalloenzyme inhibitor therapeutics, Karus has designed and developed a novel class of highly-selective inhibitors of HDAC6.

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-, functionally-, and phenotypically-distinct from the other, nuclear-expressed members of the HDAC superfamily. It has emerged as an important drug target in cancer, regulating tumor cell motility, and playing a key role in apoptosis and tumor immunology.

Selective HDAC6 inhibition promotes programmed cell death in cancer through the inhibition of aggresome formation. Inhibition of this enzyme also downregulates the tumor cell-expression of programed death-ligand 1 (PD-L1). This expression of PD-L1 is positively correlated with T cell exhaustion and tumor aggressiveness, and its presence camouflages tumors from immune cell attack.