Definition

An orally bioavailable, dual inhibitor of the nuclear enzymes poly (ADP-ribose) polymerase (PARP) 1 and 2 and microtubule polymerization, with potential antineoplastic activity. Upon oral administration, PARP/microtubule polymerization inhibitor AMXI-5001 selectively binds to and inhibits PARP-1 and -2, thereby preventing PARP-1 and -2-mediated DNA repair. This promotes genetic instability and enhances the accumulation of single and double strand DNA breaks, ultimately leading to apoptosis. In addition, the benzimidazole moiety of AMXI-5001 targets and binds to the colchicine-binding motif on tubulin, thereby inhibiting its polymerization into microtubules. This may interrupt microtubule dynamics, disrupt mitosis, lead to cell cycle arrest and induce tumor cell apoptosis. The PARP family of proteins catalyzes post-translational ADP-ribosylation of nuclear proteins and is activated by single-strand DNA (ssDNA) breaks. Microtubules play important roles in mitosis and cell division.