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 degrad

SUBMITTER: Li X 

PROVIDER: S-EPMC8994274 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature