GCN5 PCAF also directly acetylate Myc resulting in increased protein stability, Ponatinib clinical which may pro vide a positive feedback loop through GCN5 upregulation and further Myc stabilization. Both TRRAP and GCN5 are required for Myc dependent transformation and upregulation of Gcn5 by Myc contributes to the block of erythroid differentiation. These results suggest that, GCN5 and Myc co operate to block differenti ation and promote transformation. Given the import ance of GCN5 HAT complexes for Myc dependent transcription and transformation in human cells and the synthetic lethality of GCN5 deletion and CG 1521 treatment in yeast, it is likely that the effect of GCN5 knockdown combined with CG 1521 administration in Myc driven tumors will lead to the blockade of tumor progression.

GCN5 and PCAF have been shown to regulate tran scription, mediated by other transcription factors, including E2F and p53. Underlining the ver satility of the human Gcn5 homologs, GCN5 and PCAF have been shown to interact with BRCA2 and BRCA1, respectively. These HATs have been shown to modulate BRCA mediated DNA repair as well as their transcriptional activation function. GCN5 is also a potential target for oncogenic EGF signaling as it facilitates EGF mediated transcription through local ized acetylation. GCN5 and PCAF appear to be good targets for cancer therapy since they are associ ated with several proto oncogenes and are not fre quently mutated in human cancers.

Inhibitors for histone acetyltransferases are being developed and include garcinol and anacardic acid derivatives as well as synthetic inhibitors including iso thiazolones, methylene butyrolactones, and the new pyridoisothiazolone based inhibitors that appear to be very active inhibitors of PCAF. The butyrolactone MB 3 has been characterized as a GCN5 inhibitor in vitro and may be a potential treat ment for acute lymphoblastic leukemia. GCN5 SAGA interacts and acetylates the oncogene E2A PBX1 resulting in protein stabilization and in this context GCN5 inhibition results in decreased levels of the E2A PBX1 oncogene. However, as is the case with HDACis, specificity will have to be precisely determined. It will be important to determine the growth inhibitory activity of GCN5 PCAF specific in hibitors in combination with CG 1521. Conclusion We have used a high throughput yeast deletion library screen to quantify strain Batimastat growth after treatment with the HDACi CG 1521 and have identified 407 sensitive strains and 80 resistant strains. Biological processes including tran scription and chromatin remodeling are highly represented in CG 1521 sensitive strains. In particular deletion of com ponents of the SAGA complex, including Gcn5, confers sensitivity to CG 1521.