The EACR’s Top 10 Cancer Research Publications is a regular summary of the most interesting and impactful recent papers in cancer research. It is curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors.
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L. Bai et al. Cancer Cell 36, 498–511 November 11, 2019
Summary of the findings
Transcription factor signal transducer and activator of transcription 3 (STAT3) has long been pursued as a drug target but yet to be successful. Many previous efforts have focused on inhibiting the canonical activity of dimerized STAT3, which is mediated by dimerization of two phosphorylated STAT3 monomers through its Src homology 2 (SH2) domain. However, such strategy is unable to completely block the functions of STAT3 as monomeric STAT3 protein also possesses non-canonical activities. Employing the proteolysis targeting chimera (PROTAC) technology, we successfully developed SD-36 as a potent and selective STAT3 degrader. SD-36 potently and selectively degrades STAT3 protein in human normal and cancer cells in vitro, xenograft tumor tissues and mouse tissues in vivo. Comparing to its corresponding SH2 domain inhibitor, SD-36 is >1,000 times more potent in suppressing STAT3-dependent gene transcription and has much more profound effect on STAT3 target genes in cancer cells. SD-36 exerts potent growth inhibitory activities in a subset of leukemia and lymphoma cell lines with high levels of phosphorylated STAT3 protein. Importantly, SD-36 achieves complete and long-lasting tumor regression in mouse tumor models of leukemia and lymphoma cell lines and is well tolerated in animals.
Future impact of the findings
- Degradation of STAT3 protein is a promising cancer therapeutic strategy.
2. STAT3 degraders warrant clinical testing for the treatment of human cancers.
3. The PROTAC strategy can be used to develop highly selective degraders for one protein from non-selective inhibitors of homologous proteins;
4. The PROTAC strategy may be used to target other traditionally undruggable or difficult drug targets.
