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

Abstract

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.

Ferroptosis-Related lncRNA to Predict the Clinical Outcomes and Molecular Characteristics of Kidney Renal Papillary Cell Carcinoma

“…Compared to other cancer cells, renal cancer cells and leukemia cells are more susceptible to clearance. Some studies on leukemia have shown that targeted therapy has a positive effect on the treatment of leukemia [ 62 , 63 ], so our future research may be extended in the direction of leukemia treatment. However, it is important to note that the present study has limitations, primarily related to the use of transcriptome sequencing data and the relatively small sample size of single-cell data.…”

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

“…In 2022, Li et al. 143 developed novel PROTAC 69 and HyT degrader 70 targeting ENL by linking the YEATS inhibitor SGC-iMLLT 68 with thalidomide or hydrophobic tagging. PROTAC 69 efficiently degraded ENL in MV4; 11 leukemia cells, exhibiting a DC 50 of 37 nmol/L and almost complete depletion at ∼500 nmol/L ( D max ∼95%) ( Fig.…”

Chemically induced degradation of epigenetic targets

“…13). 168 Briefly, compound 1 displayed DC 50 of 37 nM and 44 nM in MV4;11 and MOLM13 cell lines, respectively. Furthermore, the degradation of ENL by compound 1 is mediated through the UPS pathway and can be rescued with either the parent inhibitor itself and thalidomide and proteosome inhibitor bortezomib.…”