247 Selective inhibitors of nuclear export (SINE) block the expression of DNA damage repair proteins and sensitize cancer cells to DNA damage therapeutic agents

Abstract

Conclusions: These studies reveal no evidence for an allosteric trapping mechanism and indicate that all PARP inhibitors examined trap PARP1 via catalytic inhibition. The potency of PARP inhibitors with respect to trapping and catalytic inhibition is linearly correlated in biochemical systems. In cells, trapping potency is related to concentrations required for potentiation in animal models. Detection of PARP trapping in cells requires supraphysiologic conditions that exhaust cellular NAD and PAR, exceed concentrations required to elicit synergism and are not tolerated in vivo. In addition trapping potency appears to be inversely correlated with tolerability. Quantitation of the degree of trapping that is tolerable and is required for therapeutic benefit is under active investigation. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.