A proteolysis-targeting chimera molecule selectively degrades ENL and inhibits malignant gene expression and tumor growth

• Main Authors: Li, X. (Author), Song, Y. (Author), Wu, F. (Author), Yao, Y. (Author)
• Format: Article
• Language: English
• Published: BioMed Central Ltd 2022
• Subjects: acute myeloid leukemia; AFF4 protein, human; animal; Animals; Cancer therapeutics; carcinogenesis; Carcinogenesis; chemistry; chimera; Chimera; ENL; ENL mutation; gene expression; Gene Expression; genetics; human; Humans; Kidney Neoplasms; kidney tumor; Leukemia, Myeloid, Acute; metabolism; Mice; mixed lineage leukemia protein; MLL1-rearranged leukemia; mouse; Myeloid-Lymphoid Leukemia Protein; nephroblastoma; PROTAC; protein degradation; Proteolysis; transcription elongation factor; Transcriptional Elongation Factors; Wilms Tumor
• Online Access: View Fulltext in Publisher

 Background: Chromosome translocations involving mixed lineage leukemia 1 (MLL1) cause acute leukemia in most infants and 5–10% children/adults with dismal clinical outcomes. Most frequent MLL1-fusion partners AF4/AFF4, AF9/ENL and ELL, together with CDK9/cyclin-T1, constitute super elongation complexes (SEC), which promote aberrant gene transcription, oncogenesis and maintenance of MLL1-rearranged (MLL1-r) leukemia. Notably, ENL, but not its paralog AF9, is essential for MLL1-r leukemia (and several other cancers) and therefore a drug target. Moreover, recurrent ENL mutations are found in Wilms tumor, the most common pediatric kidney cancer, and play critical roles in oncogenesis. Methods: Proteolysis-Targeting Chimera (PROTAC) molecules were designed and synthesized to degrade ENL. Biological activities of these compounds were characterized in cell and mouse models of MLL1-r leukemia and other cancers. Results: Compound 1 efficiently degraded ENL with DC50 of 37 nM and almost depleted it at ~ 500 nM in blood and solid tumor cells. AF9 (as well as other proteins in SEC) was not significantly decreased. Compound 1-mediated ENL reduction significantly suppressed malignant gene signatures, selectively inhibited cell proliferation of MLL1-r leukemia and Myc-driven cancer cells with EC50s as low as 320 nM, and induced cell differentiation and apoptosis. It exhibited significant antitumor activity in a mouse model of MLL1-r leukemia. Compound 1 can also degrade a mutant ENL in Wilms tumor and suppress its mediated gene transcription. Conclusion: Compound 1 is a novel chemical probe for cellular and in vivo studies of ENL (including its oncogenic mutants) and a lead compound for further anticancer drug development. © 2022, The Author(s).