P1, N=120, Active, not recruiting, Kymera Therapeutics, Inc. | Recruiting --> Active, not recruiting

Treatment with a clinical-stage STAT3 degrader, KT-333 resulted in a significant reduction in STAT3 and MCL1 protein levels within two weeks of treatment in a cell derived xenograft model of Ven-res AML. Our prior research demonstrated STAT3 over-expression in AML HSPC's to be associated with inferior survival. We now explore STAT3 over-expression in Ven-res AML, explain STAT3 mediated mitochondrial perturbations and describe a novel therapeutic strategy, STAT3 degradation to overcome Ven-res.

Acute myeloid leukemia (AML) cells resist differentiation stimuli despite high expression of innate immune receptors, such as Toll-like receptor 9 (TLR9). In fact, the combination of DNA methyl transferase (DNMT) inhibition using azacitidine with CpG oligonucleotides alone mimicked CpG-STAT3d effects, resulting in AML cell differentiation, T cell activation, and systemic leukemia regression. These findings highlight immunotherapeutic potential of bi-functional oligonucleotides to unleash TLR9-driven differentiation of leukemic cells by concurrent STAT3 and/or DNMT inhibition.

The PROTAC prodrugs were activated by the upregulated ROS levels in CSCs and efficiently degraded STAT3 for chemical reprogramming, which would not only impair their stemness features but also remodel the immunosuppressive TME into an immunosupportive state to boost anti-HCC immunity. This strategy provides an approach for improving HCC treatment in clinics.

Ven is FDA approved in combination with hypomethylating agents (HMA's) or low dose cytarabine for the treatment of de-novo AML in patients > 75 years or those ineligible for standard induction therapies...Additionally, cell derived xenograft (CDX) models of Ven-res showed significant reduction of pTyr-705 STAT3(~60%), total STAT3 (>90%) and MCL1 (~70%), on treatment with STAT3 degrader - KT-333 (currently in an early phase clinical trial:NCT05225584), as early as week 2 (Fig 1B). Our study suggests that targeting STAT3 and the downstream MCL1 represents a novel and effective strategy for Ven-resistant AML patients in clinic, with strong mechanistic rationales that can spur further clinical development of STAT3 degraders especially given the significant side effects of direct MCL1 inhibitors.

The emerging clinical data demonstrate that KT-333 is a potent degrader of STAT3 as demonstrated in PBMCs at doses that are well tolerated. These data provide the first evidence of STAT3 targeted protein degradation in humans with associated STAT3 pathway inhibition, along with potential early signs of antitumor activity, highlighting the potential of heterobifunctional degraders for targeting previously undruggable transcription factors implicated in diseases. Based on non-clinical data and PK/PD modeling, the high levels of degradation achieved so far are expected to be clinically efficacious in STAT3-dependent malignancies.

The emerging clinical data suggest that KT-333 is a potent degrader of STAT3 as demonstrated in PBMCs at doses that are well tolerated. These data provide the first evidence of STAT3 targeted protein degradation in humans and point to the potential of heterobifunctional degraders for targeting previously undruggable targets. It is projected that higher doses of KT-333 will achieve the predicted degradation profile in tumors that may translate into clinical benefit in patients with STAT3-dependent T cell malignancies.

HZ-R078 is a selective and potent STAT3 degrader which has tumor-enriched distribution character. The pre-clinical efficacy and safety study support its further development in clinical stage for T-cell lymphoma therapy.

Quercetin has a potential future in chemoprevention, based on substantial research on its anticancer effects. The current review discusses quercetin's mechanisms of action, nanodelivery strategies, and other potential cellular effects in liver cancer.

CD45 repression was mediated by STAT3 as demonstrated by ChIP-seq data on ALCL cells treated with the ALK-TKI crizotinib or cells treated with a STAT3 degrader. Next, we found that knocking-out CD45 with the CRISPR/Cas9 system resulted in increased resistance to ALK TKI treatment and CD45 was down-regulated in ALCL cells that developed resistance in vitro to ALK TKIs. Overall, these data suggest that CD45 expression is regulated by ALK via STAT3 and acts as a rheostat of ALK oncogenic signaling and resistance to TKI treatment in ALCL.

Enrollment in the Phase 1a portion of the study is ongoing. NCT05225584

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...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.

Fig Legend: Treatment of mice exhibiting CTCL phenotypes starting at ~3mo of age. Phenotype score reflects presentation of fur loss, scaling/flaking of the skin, appearance of lesions and death.

We first synthesized an analog of the STAT3 inhibitor S3I-201 as a ligand, using the cereblon (CRBN)/cullin 4A E3 ligase ligand pomalidomide to synthesize a series of PROTACs. Among them, the SDL-1 achieves the degradation of STAT3 protein in vitro, and exhibits good anti-gastric cancer cell proliferation activity, inhibits invasion and metastasis of MKN1 cell, and induces MKN1 cell apoptosis and arrests cell cycle at the same time. Our study shows that SDL-1 is a potent STAT3 degrader and may serve as a potential anti-gastric cancer drug, providing ideas for further development of drugs for clinical use.

Our findings indicate that luteolin inhibits STAT3 signaling by suppressing STAT3 activation and promoting STAT3 protein degradation in melanoma cells, thereby exhibiting anti-melanoma effects. This study provides further pharmacological groundwork for developing luteolin as a chemopreventive agent against melanoma.

Phthalimide derivatives, such as thalidomide, were tethered to the 3’ end of the decoy molecule without or with aliphatic linkers of different length...To our knowledge, this is the first demonstration that the PROTAC strategy can be employed to decoy DNA-based targeting of undruggable TFs. Our initial results underscore the potential of using this strategy for cell-selective targeting of oncogenic and immunosuppressive STAT3 with potential application to cancer immunotherapy.

Moreover, NCT-80 inhibited chemotherapy- and EGFR TKI-induced programmed cell death ligand 1 expression and potentiated the antitumor effect of chemotherapy in the LLC-Luc allograft model. These data indicate the potential of STAT3/Wnt signaling pathway as a target to overcome resistance to Hsp90 inhibitors and NCT-80 as a novel Hsp90 inhibitor that targets both CSCs and non-CSCs in NSCLC.

Meanwhile, Nar-loaded nanoparticles could markedly decrease the protein levels of STAT3 in tumors, resulting in significantly increased MCF-7/TR xenograft tumor regression without obvious toxicity. Our findings successfully highlight the STAT3 as the direct therapeutic target of Nar in ER-positive breast cancer cells, especially, Nar leaded STAT3 degradation as a promising strategy for the tamoxifen-resistant breast cancer treatment.

PDLIM2 has also been explored as a therapeutic target for cancer therapy. At the end of this review, we provide perspectives on this important molecule and discuss the future directions of both basic and translational studies.

FDA approved therapies such as the recently approved Bcl-2 inhibitor venetoclax, FLT3 inhibitors, among others, have moved the field forward in newly diagnosed MDS/AML...We have successfully demonstrated that a selective antisense oligonucleotide inhibitor of STAT3, Danvatirsen, is rapidly incorporated into MDS/AML HSPCs and induces selective apoptosis and downregulation of STAT3 in these cells in comparison with healthy control HSPCs...Through the generation of a STAT3C-vavCre mouse model, that recapitulates the features of MDS/AML, we aim to further our understanding of the molecular mechanisms and pathways that play an important role in MDS to AML transformation and will help us identify downstream mediators of this event that can be therapeutically targeted. We would also like to use this murine model as an ideal substrate for preclinical studies of STAT3 targeting therapies in hematologic malignancies such as previously reported antisense inhibitors of STAT3 and STAT3 degraders.

Conclusions STAT3 degradation remodels an immunosuppressed TME activating anti-tumor immunity as monotherapy and effectively combines with anti-PD1. These data provide a rationale for selectively degrading STAT3 as a strategy to sensitize cancers with relevant immune contextures to ICT in the clinic.