Benzofuranoindoline-Containing Fungal RiPP-Derived Anticancer Compounds

Benzofuranoindoline-containing fungal RiPP-derived compounds and analogs, plus pharmaceutical compositions, and administration methods for treating cancers, including leukemia.
Problem:
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.
Solution:
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.
Technology Overview:
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.
Advantages:

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

Applications:

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