Deciphering the Potency of LP-284: A Novel Chiral DNA Alkylating Agent in Hematologic Malignancies

LP-284, the synthetic enantiomer of acylfulvene compound LP-184, has been identified as a highly effective agent against hematologic cancers. It demonstrates superior antiproliferative effects compared to five other acylfulvenes, including its natural counterpart. The unique potency of LP-284 may stem from its distinct metabolic activation, transport mechanisms, or interactions with cellular components. Our study investigated the role of Prostaglandin Reductase 1 (PTGR1), an enzyme that activates Irofulven, in relation to the sensitivity of LP-284. We discovered a strong correlation between PTGR1 expression and the sensitivity to LP-184 and Irofulven, but not to LP-284. PTGR1 expression was notably lower in hematologic cancer cells, suggesting another activator for LP-284 in these cells.

A comprehensive analysis of 489 oxidoreductases revealed no significant correlation with LP-284 activity. LP-284 showed remarkable efficacy in cell viability assays across various hematologic cancer types, with particularly potent effects on acute lymphocytic leukemia, chronic myeloid leukemia, B-cell lymphoma, and Multiple Myeloma (MM). The combination of LP-284 with spironolactone, a hypertension drug, was explored for its therapeutic potential in MM. Spironolactone degrades ERCC3, a key component of the TC-NER pathway, which enhances the cytotoxicity of LP-284 by making cells more susceptible to DNA lesions.

The findings underscore the significance of stereochemistry in acylfulvene efficacy and highlight LP-284 as a promising candidate for treating hematologic cancers. The drug's potential to induce DNA damage that is lethal to cells with impaired DNA repair mechanisms and to inhibit transcription of essential fusion genes until repair is completed, positions LP-284 as a potential targeted therapy for cancers with compromised DNA repair capabilities.