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Oral administrations of STX 0119 arrested the growth of human lymphoma cells in a SCC 3 subcutaneous xenograft model through inhibition of STAT3 activity, Shin et al. searched within the natural compounds using a dual luciferase assay to describe novel and spe cific inhibitor of STAT3. Cryptotanshinone, derived from roots of Salvia miltiorrhiza Bunge, was 17-AAG ic50 identified as a potent STAT3 inhibitor. Cryp totanshinone inhibited STAT3 activity in a dose dependent manner in HCT 116 colon cancer cells with an IC50 value of 4. 6 uM. Activity of STAT3 was also inhibited in breast, prostate and cervical cancer cell lines. Study of binding mechanism revealed that crypto tanshinone directly interact with SH2 domain of STAT3 to inhibit Tyr705 phosphorylation and prevents STAT3 dimerization and nuclear translocation, Curcumin, a component of the golden spice turmeric, can modulate multiple cell sig naling pathways.<br><br> Promising effects of Adriamycin 25316-40-9 this compound are seen in many conditions including cardiovascular diseases, arthritis, uveitis, inflammatory bowel disease, and in differ ent types of cancers, However, it is not readily absorbed from the gut after oral administration and has limited tissue distribution. This inspired many to de velop compounds analogous to curcumin with better pharmacokinetics, including FLLL11, FLLL12, FLLL32 and FLLL62, These analogues selectively bind to STAT3 SH2 domain to inhibit phosphorylation of Tyr705 and prevent its dimerization and downstream functioning.<br><br> They are more potent ABT-199 than curcumin and shown to inhibit growth of many human cancer cell lines including pancre atic, breast, renal cell, hepatocellular, squamous cell cancer of head neck region, colorectal, melanoma, myeloma, glioblastoma, osteosarcoma, and rhabdomyosarcoma, One chemical library with 920,000 small drug like compounds virtually screened by docking each into the peptide binding pocket of the STAT3 SH2 domain, the compounds C3, C30, and C188 were found to be active in inhibiting IL 6 mediated phosphorylation of STAT3 with an IC50 of 91, 18 and 73 uM respectively, As C188 was the most potent, Redell et al. performed similarity screening using C188 scaffold followed by 3 D pharmacophore analysis and identified more potent compounds. Among these second generation com pounds, C188 9, inhibited G CSF induced STAT3 phos phorylation with low micromolar potency.<br><br> IC50 of C188 9 in several AML cell lines ranged from 4. 1 uM to 8. 3 uM, More recently Li and colleagues developed a novel STAT3 SH2 dimerization inhibitor by utilizing in silico site directed fragment based drug design. They utilized naphthalene 5,8 dione 1 sulphoneamide fragment of compound LLL12 as binding moiety to pTyr705 of STAT3 SH2 domain and linked it to a dimethyl amine with an R group. Based on differences in R group they developed 5 different compounds. One of these com pounds found to be more potent than control, easy to synthesize and possessed more drug able proper ties, Unfortunately, these STAT3 inhibitors are still not po tent enough or drugable to be examined in clinical studies. Inhibitors targeting STAT5 SH2 binding domain Similar to the development of STAT3 inhibitors, Berg et al.