Small Molecule-Induced, Selective STAT3 Degradation Leads to Anti-Tumor Activity in STAT3-Dependent Heme Malignancies (2019)

Targeted protein degradation mediated by small molecule degraders represents a new and exciting therapeutic modality to target difficult-to-drug oncogenic proteins including transcription factors. These molecules bind to both the target protein and an E3 ligase, enabling the formation of a ternary complex that leads to ubiquitination and subsequent degradation of the target protein by the proteasome. STAT3 (signal transducers and activators of transcription 3) is a transcription factor and a member of the STAT protein family. In response to cytokines and growth factors, STAT3 is phosphorylated by receptor-associated serine/threonine kinases, and phosphylated STAT3 (pSTAT3) then forms dimers that translocate into the nucleus, binds to DNA, and regulate transcription. STAT3 is frequently mutated and activated in numerous cancers including clinically aggressive hematologic malignancies with high unmet medical need. Mechanistically, aberrant activation of STAT3 has been directly linked to the promotion of cancer cell survival, proliferation and immune evasion, thus making it a highly attractive target for oncology. Potent and selective agents specifically and directly targeting STAT3 have remained elusive, however. Herein we report the discovery of a potent and selective STAT3 heterobifunctional degrader, KYM-003, which displays strong anti-tumor activity in models of STAT3-dependent heme malignancies. KYM-003 degrades STAT3 via an E3 ligase-dependent mechanism. It strongly binds to STAT3 and a E3 ligase, leading to the formation of the a productive ternary complex, which leads to ubiquitination of STAT3 and subsequent proteasomal degradation. KYM-003 robustly degraded STAT3 in a number of primary cells or cell lines with DC50 &lt; 100 nM. Degradation was highly selective for STAT3 vs &gt;10,000 other detected proteins (including all other STAT family members) in cell lines and human PBMCs. Degradation of STAT3 by KYM-003 led to significant downregulation of STAT3 target genes, such as SOCS3, MYC, and PIM1. Importantly, total STAT3 and pSTAT3 levels in tumors were reduced by &gt;90% for at least 24 hours after a single dose of KYM-003 and repeated dosing of KYM-003 showed dose-dependent antitumor activity in xenograft models of heme malignancies. Collectively, our data demonstrates that KYM-003 is a potent and selective STAT3 degrader that exhibited strong anti-tumor activity in vitro and in vivo. These data support STAT3 degraders as a new and exciting therapeutic opportunity in heme malignancies. Disclosures Csibi: kymera Therapeutics: Employment, Equity Ownership. Ji:Kymera Therapeutics: Employment, Equity Ownership. Yang:Kymera Therapeutics: Employment, Equity Ownership. Yuan:Kymera Therapeutics: Employment, Equity Ownership. Mayo:kymera Therapeutics: Employment, Equity Ownership. Rong:Kymera Therapeutics: Employment, Equity Ownership. Rusin:Kymera Therapeutics: Employment, Equity Ownership. Sharma:kymera Therapeutics: Employment, Equity Ownership. Loh:Kymera Therapeutics: Employment, Equity Ownership. Li:Kymera Therapeutics: Employment, Equity Ownership. Townson:Kymera Therapeutics: Employment, Equity Ownership. Chen:kymera therapeutics: Employment, Equity Ownership. Kamadurai:Kymera Therapeutics: Employment, Equity Ownership. Walker:Kymera Therapeutics: Employment, Equity Ownership. Gollob:Kymera Therapeutics: Employment, Equity Ownership. Mainolfi:Kymera Therapeutics: Employment, Equity Ownership.