Genomic deletions are ubiquitous in the cancer genome, often inactivating tumor suppressor genes. An unintended consequence of these deletions is the co-deletion of nearby chromosomal neighbors that are irrelevant to tumor progression. Our lab has pioneered a novel therapeutic strategy that targets tumor suppressor deletions by exploiting vulnerabilities generated by the co-deletion of neighboring metabolic housekeeping genes with critical but normally redundant functions. One promising passenger deletion is of the glycolytic enzyme ENO1 in a subset of glioblastomas. Cancers harboring the deletion of ENO1 are dramatically sensitized to inhibition of its redundant paralog, ENO2. To therapeutically actionize on this vulnerability, we generated a substrate-competitive phosphonate inhibitor of ENO2, termed HEX, which 4-fold specificity for ENO2 over ENO1 (Ki of 63 nM vs. 250 nM). As a phosphonate inhibitor, HEX is negatively charged at physiological pH, hampering cell and tissue permeability. In vivo proof-of-principle with HEX shows that inhibition of ENO2 in ENO1-deleted orthotopic xenografted mice is capable of eradicating tumors. This presentation will describe current efforts to translate HEX to the clinic. A comparison of various prodrug delivery strategies to improve the delivery of HEX will be considered in the context of its pharmacokinetics across species.

Targeted inhibition of enolase 2 for the treatment of ENO1-deleted cancers

ACS Fall 2021

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