Benzofuranoindoline-containing fungal RiPP-derived compounds and analogs, plus pharmaceutical compositions, and administration methods for treating cancers, including leukemia.

The disclosure targets diseases and disorders where new therapeutic compounds are needed, including cancers such as leukemia. Fungal ribosomally synthesized and post-translationally modified peptides (RiPPs) can show potent bioactivity and structural diversity. Identification of fungal RiPPs has been hindered by limited biosynthetic knowledge and a lack of efficient toolboxes. This limits conversion of fungal genomic potential into characterized developable compound leads.

This disclosure provides compounds of Formula (I) and analogs, and pharmaceutical compositions comprising a disclosed compound and an excipient. Methods are provided for treating or preventing a disease or disorder by administering a pharmaceutically effective amount to a patient in need thereof. In some embodiments, the disease or disorder is cancer, including leukemia. The disclosure describes N-terminal substitutions, including fatty-acid conjugation, which improves in vitro cytotoxicity for certain analogs.

The technology covers benzofuranoindoline-bearing fungal RiPP-related compounds defined by Formula (I), including multiple substituent options and specific embodiments. The disclosure describes generating analogs, including through precursor peptide engineering and N-terminal modifications. In vitro evaluation is described for certain variants, including one lipidized analog with reported IC₅₀ values ranging from 40 to 99 nm against three leukemia cell lines. The disclosure also describes pharmaceutical compositions, dosing concepts, and multiple administration routes for the compounds.

• Specify a Formula (I) structure with variable substituents, enabling broad analog coverage and named embodiments
• Improve in vitro cytotoxicity through N-terminal substitution, including fatty-acid conjugation, with reported nanomolar IC₅₀ values in certain leukemia cell lines
• Includes pharmaceutical compositions with excipients and administration approaches across multiple delivery routes

• Leukemia therapeutics: Administer disclosed compounds or compositions to treat leukemia, including embodiments reporting IC₅₀ values ranging from 40 to 99 nm against three leukemia cell lines
• Cancer treatment methods: Use the disclosed administration methods to treat cancers described in the disclosure, using a pharmaceutically effective amount of a compound or composition
• RiPP analog development: Generate additional analogs via precursor peptide engineering and N-terminal modification strategies described for producing and studying related compounds
• Drug product formulation: Formulate compounds with excipients into dosage forms for oral, parenteral, topical, or inhaled administration routes described in the disclosure