Many sarcomas and leukemias carry non-random chromosomal translocations encoding mutant fusion transcription factors that are essential to their molecular pathogenesis. These novel, tumor-specific proteins provides a unique opportunity for the development of highly selective anticancer drugs that has yet to be exploited. A particularly clear example is provided by Ewing's Sarcoma Family Tumors (ESFT) which contain a characteristic t(11;22) translocation leading to expression of the oncogenic fusion protein EWS-FLI1. EWS-FLI1 is a disordered protein that precluded standard structure-based small molecule inhibitor design. Using surface plasmon resonance screening, we discovered a lead compound, NSC635437. A derivative compound, YK-4-279, blocks RHA binding to EWS-FLI1, induces apoptosis in ESFT cells, and reduces the growth of ESFT orthotopic xenografts. These findings provide proof of principle that inhibiting the interaction of mutant cancer-specific transcription factors with the normal cellular binding partners required for their oncogenic activity provides a promising strategy for the development of uniquely effective, tumor-specific anticancer agents.

is an absolute requirement for the downstream activities of the major base excision repair enzymes, it may act as a regulator for the base excision repair pathway for efficient and balanced repair of damaged bases, which are often less toxic and/or mutagenic than their subsequent repair product intermediates.Cellular DNA is continuously exposed to endogenous or exogenous chemical or physical agents that induce DNA lesions. DNA base damage threatens genomic stability and cellular viability. Multiple DNA repair pathways exist in all organisms, from bacteria to humans, to preserve the integrity of the genome (1). If not repaired, damaged bases could be mutagenic (2) and/or cause cell death by blocking DNA replication (3).In all organisms, repair of DNA-containing small adducts, as well as altered and abnormal bases, occurs primarily via the base excision repair (BER) 2 pathway, beginning with cleavage of the base by a DNA glycosylase (1, 2). Mechanistically, DNA glycosylases are categorized into two classes: mono-and bifunctional DNA glycosylases. Monofunctional DNA glycosylases, such as N-methylpurine-DNA glycosylase (MPG) and uracil-DNA glycosylase, use an activated water molecule as a nucleophile to generate an apurinic or apyrimidinic (AP) site in DNA. Bifunctional DNA glycosylases/AP lyases, such as NTH1 and OGG1, use an activated amino group (Lys) or imino group (Pro) as the nucleophile to create a Schiff base intermediate that coordinates base removal and subsequent strand incision (AP lyase) 3Ј to the AP site (4, 5). The mammalian MPG is known to excise at least 17 structurally diverse modified bases from DNA (6). These lesions include 3-alkylpurines, 7-alkylguanine, 1,N 6 -ethenoadenine (⑀A), N 2 ,3-ethenoguanine, and hypoxanthine (Hx), all of which are purine derivatives (7-12). Moreover, the base alterations are located in both the major and minor grooves of duplex DNA. Its orthologs in Escherichia coli (AlkA) and yeast (MAG) have an overlapping although not identical substrate range. Nonetheless mammalian MPG and E. coli AlkA do not share significant sequence similarity or structural homology (13,14), despite this functional similarity and the fact that 3-methyladenine is a preferred substrate for both. MPG excises ⑀A and Hx more efficiently than AlkA and MAG (11), but unlike AlkA, it cannot excise O 2 -alkylpyrimidines (15, 16) and oxidized bases such as 5-formyluracil and 5-hydroxymethyluracil (17) (22); however, the reduction was more pronounced for the AP-lyase activity. The Schiff base formation between hOGG1-and 8-oxoG-containing DNA was abrogated in the presence of Mg 2ϩ . These results suggest that hOGG1 operates mainly as a monofunctional glycosylase under physiologic concentrations of Mg 2ϩ (22). There