Dual specific STAT3/5 degraders effectively block acutemyeloid leukemia and natural killer/T cell lymphoma

Daniel Pölöske, Helena Sorger, Anna Schönbichler, Elvin D. de Araujo, Heidi A. Neubauer, Anna Orlova, Sanna H. Timonen, Diaaeldin I. Abdallah, Aleksandr Ianevski, Heikki Kuusanmäki, Marta Surbek, Elisabeth Heyes, Thomas Eder, Christina Wagner, Tobias Suske, Martin L. Metzelder, Michael Bergmann, Maik Dahlhoff, Florian Grebien, Roman Fleck, Christine Pirke, Walter Berger, Emir Hadzijusufovic, Wolfgang R. Sperr, Lukas Kenner, Peter Valent, Tero Aittokallio, Marco Herling, Satu Mustjoki, Patrick T. Gunning and Richard Moriggl

Abstract:
The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression andactivation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focuson blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activationand frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX‐0700 andJPX‐0750 as dual STAT3/5 binding inhibitors promoting protein degradation. JPX‐0700/−0750 decreased the mRNA andprotein levels of STAT3/5 targets involved in cancer survival, metabolism, and cell cycle progression, exhibiting nanomolar to lowmicromolar efficacy. They induced cell death and growth arrest in both AML/NKCL cell lines and primary AML patient blasts.We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in kinases,activating mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti‐apoptotic, pro‐proliferative,or epigenetic‐modifying STAT3/5 targets. This emphasizes a vicious cycle for proliferation and survival through STAT3/5. BothJPX‐0700/−0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly,being well tolerated by mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics inAML/NKCL cells.

The publication can be found  here.