HZ-R061, a Selective STAT3 Degrader with Activity in Preclinical Model of Hematologic Malignances

Abstract

The Janus kinase/Signal transducer and activator of transcription (JAK-STAT) pathway is one of the core cancer pathways that integrates signals from cytokines, hormones and growth factors to induce or repress gene expression in cells . The pathway consists of four JAK kinases and seven STAT transcription factors (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6). STAT3 is the best-studied family member of the JAK-STAT pathway in cancer, and is a known oncogene in various types of tumor. So STAT3 is an attractive cancer therapeutic target, great efforts have been made to discover effective STAT3 inhibitor. However most of reported STAT3 inhibitors got failed for further development due to the low selectivity, weak binding affinity or poor drugability. STAT3 is considered as an undruggable target for long time. Recently, the proteolysis targeting chimeras (PROTAC) strategy has gained momentum for its promise in the discovery and development of an entirely new type of therapeutics for the treatment of human diseases. PROTAC molecule is a bifunctional small molecule designed to recruit cellular degradation machinery to induce targeted protein degradation in a catalytical way. PROTAC can be a new strategy to effectively target undruggable targets such as STAT3. HZ-R061 is a novel STAT3 selective degrader which is discovered and developed through our DaTProD® platform which was set up to promote PROTAC development. HZ-R061 can selective and effective degrade STAT3 in various types of cells including MOLM16, A549, SU-DHL1, karpas299, LY3, THP1 and human PBMC with DC50 values at nanomolar level. In in-vitro anti-proliferative assay, HZ-R061 exhibits potent anti-proliferative activity against CTCL and AML cell lines. Furthermore, MOLM16, SU-DHL1 and Karpas299 xenograft models were used for in-vivo anti-tumor evaluation. After IV administration of HZ-R061 (QW), the growth of tumor was significantly suppressed in all three models. As STAT3 is a master regulator in tumor microenvironment, inhibition of STAT3 could remodel TME towards in favor of anti-cancer. The combination of HZ-R061 with PD-(L)1 mAb was also conducted in CT26 model. HZ-R061 exhibits significantly synergistic effect in combination with PD-(L)1 mAb. Additionally, HZ-R061 also potently decreases phosphorylation level of STAT3 in IL-6 stimulated THP-1 cells with IC50 value of 3.8nM, which is 50 folds stronger than JAK inhibitor Ruxolitinib. HZ-R061 also shows strong effect in in-vitro Th17 differentiation assay and EAE model. These results suggest that HZ-R061 is also a promising drug candidate for various Th17 driven auto-immune diseases including MS, RA, SSc and IPF. In conclusion, we discovered a pre-clinical effective STAT3 degrader HZ-R061, which has potential for further development in tumor and auto-immune diseases.