Background Platinum compounds, such as cisplatin and carboplatin, are DNA interstrand crosslink selleck inhibitor inducing agents. ICLs bind both strands of the DNA helix, inhibit DNA replication and RNA tran scription, and induce cell cycle arrest and apoptosis. Platinum compounds are widely used for the Inhibitors,Modulators,Libraries treatment of multiple cancers, including ovarian, testicular, Inhibitors,Modulators,Libraries lung and some pediatric tumors. Ovarian cancers initially respond very well to platinum based therapy. However, many patients with ovarian cancer eventually relapse with platinum resistant disease. Various platinum resistance mechanisms have been proposed, including restoration of DNA repair. Therefore, combination therapy using small molecules that inhibit DNA repair pathways responsible for cellular resistance to ICLs, such as Fanconi anemia pathway inhibitors, is a logical strategy to overcome and prevent platinum resistance.

FA is a rare genetic disease characterized by chromo somal instability, cancer susceptibility, aplastic anemia and cellular hypersensitivity to ICLs. The 15 FA proteins cooperate in the FA pathway, which coordinates mul tiple DNA repair mechanisms Inhibitors,Modulators,Libraries including endonuclease mediated DNA processing, translesion DNA synthesis and homologous recombination. Monoubiquitination and nuclear foci formation of FANCD2 and FANCI are crucial steps in the activation of this pathway. The USP1/UAF1 deubiquitinase complex deubiquitinates FANCD2 and reverses the FA pathway activation. Mutation and silencing of genes controlling the FA pathway have been linked to the development of tumors, and are associated with increased ICL sensitivity.

Restoration of an intact FA pathway leads to the emergence of ICL resistant tumors. Thus, small molecules that inhibit the FA pathway may function as platinum chemo sensitizers and have clinical utility in restoring platinum sensitivity Inhibitors,Modulators,Libraries of tumor cells. We have developed a cell based screening assay for small molecules that inhibit the FA pathway, and pub lished partial results Inhibitors,Modulators,Libraries focusing on one of the hits, curcumin. Monoketone analogs of curcumin were subsequently shown to have potent FA pathway inhibitory effects. A cell free screening assay using Xenopus egg extract also identified 2,3 dichloro 5,8 dihydroxy 1,4 naphthoquinone as an FA pathway inhibitor. Recently, the Nedd8 activated enzyme inhibitor MLN4924 was shown to sensitize cells to DNA damaging agents through indirect inhibition of the Fanconi anemia pathway.

However, despite important efforts, no specific inhibitor of the FA pathway has been identified so far. In the current study, using a human cell based assay, we completed screening of more than 16,000 chemicals for molecules that inhibit the FA pathway, and identified 26 small molecules that inhibit ARQ197 clinical trial ionizing radiation induced FANCD2 foci formation.