Signal Transducer and Activator of Transcription 5 (STAT5) is an inducible transcription factor that plays a pivotal role in the progression of many cancers, including acute and chronic myeloid leukemia (AML, CML). Kinase oncoproteins activated by human leukemia-relevant genetic alterations signal to activate STAT5, and genetic experiments have shown that STAT5 is a requisite downstream effector of these oncoproteins in a major fraction of adult leukemia. While the genetic data are compelling, genetic deletion is not a functional therapy in humans. Proving that STAT5 is a target for the treatment of leukemia requires the use of chemical STAT5 inhibitors in vivo. Drugs targeting upstream STAT5-activating kinases met with initial success, but are plagued with acquired resistance, off-target toxicity associated with poor kinase selectivity, and alternative oncogenic pathways activating STAT5. Moreover, they do not directly inhibit STAT5. A central concept underlying this proposal is that small molecule binding to the STAT5-SH2 domain inhibits STAT5 activation, resulting in a blockade to STAT5 activity. We hypothesize that interrogating our STAT5-SH2 domain inhibitor platform using an integrated medicinal chemistry and leukemia modeling approach will derive the first STAT5- targeted small molecule inhibitor for the in vivo dissection of cancer biology. We expect to validate STAT5 as a bona fide target for the treatment of leukemia, and to provide succinct STAT5-regulated biomarkers to evaluate STAT5-inhibitor efficacy in the context of human AML.
Genetic experiments have identified STAT5 as a pivotal target for intervention in both leukemia and solid organ cancers. Given that available STAT5 inhibitor compounds are of limited efficacy, there is a dire need to develop robust in vivo chemical tools for blocking STAT5 to translate the genetic data.
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| Muench, David E; Grimes, H Leighton (2015) Transcriptional Control of Stem and Progenitor Potential. Curr Stem Cell Rep 1:139-150 |
| Cumaraswamy, Abbarna A; Lewis, Andrew M; Geletu, Mulu et al. (2014) Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein. ACS Med Chem Lett 5:1202-1206 |
