Transducer and Activator of Transcription 5 (STAT5) is a transcriptional factor and has been
proposed as an attractive cancer therapeutic target. However, successful of targeting STAT5
has proven to be very challenging. In recent years, induced protein degradation has emerged as
an effective strategy for targeting those traditional “undruggable” or difficult therapeutic targets.
In this R01 award, we propose to design and develop small-molecule degraders of STAT5. Our
preliminary data have demonstrated that our designed STAT5 degraders potently and
selectively induce STAT5 degradation in human cancer cells and in xenograft tumor tissue in
vivo, leading to effective inhibition of STAT5 function. Importantly, our best STAT5 degrader is
effective in inhibition of cell growth in human CML and AML cell lines with hyperactive STAT5
and is capable of inducing tumor regression in mice at well tolerated dose-schedules.
Determination of co-crystal structures of both STAT5 ligands and degraders in complex with
STAT5 provides us with a solid structural basis for further optimization. Our ultimate goal of this
R01 award is to develop a highly potent, selective, and optimized STAT5 degrader for the
treatment of human CML, AML and other types of human cancers with hyperactive STAT5. To
achieve our goal, we propose to the following specific Aims:
Aim 1: Structure-based design and synthesis of new STAT5 degraders to further optimize
degradation potency, selectivity, pharmacokinetics, and in vivo efficacy.
Aim 2: Investigation of the in vitro activity, specificity, and mechanism of action of new STAT5
degraders using human cancer cell lines containing different levels of activated STAT5 protein.
Aim 3: Determination of the metabolic stability, pharmacokinetics, pharmacodynamics, and in
vivo anticancer activity of STAT5 degraders in mouse models and their potential toxicity in mice.
To the best of our knowledge, our laboratory is the first to develop PROTAC small-molecule
STAT5 degraders. Successfully performed, this project will bring a first-in-class, highly optimized
STAT5 small-molecule degrader into advanced preclinical development and clinical trials as a
new therapy for the treatment of human cancers with activated STAT5.