# Discovery and characterization of synthetic bioinformatic natural product anticancer agents

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2024 · $401,983

## Abstract

Many of our most important therapeutics were inspired by bacterial small molecules (natural products, NPs).
Although microbial NPs display a wide range of bioactivities, they have offered their greatest utility as anticancer
agents and antibiotics. The incredible success of NPs as lead structures for therapeutic development is thought
to be due to their unique structural and mode of action refinement from eons of evolutionary selective pressures.
Since many drug discovery programs deprioritized NPs due to unacceptably high rediscovery rates, bioinformatic
analyses of genomic sequence data, whether from cultured bacteria or metagenomes, has revealed that the
biosynthetic diversity accessed by traditional monoculture fermentation studies represents only a small fraction
of the NPs that are actually encoded by the global microbiome. Unlocking the metabolites encoded by this large
fraction of previously inaccessible biosynthetic gene clusters (BGCs) should provide structurally and
mechanistically novel molecules that can serve as inspirations for new anticancer agents. Traditional NPs
discovery methods rely on biological processes (i.e., transcription, translation and enzymes) to convert genetic
instructions contained in bacterial genomes into novel bioactive small molecules. Unfortunately, with these
methods it has not been possible to coax laboratory grown bacteria into producing all the different NPs they are
capable of making. We have therefore developed a “biology free” discovery approach where, instead of decoding
genetic instructions using biological processes, bioinformatic algorithms are used to predict the chemical
structures produced by bacteria and then chemical synthesis is used to build these structures, which we have
called Synthetic Bioinformatic NPs (syn-BNPs). This proposal is designed to bring together advanced
bioinformatics, total chemical synthesis, and next-generation metagenomic methods to identify syn-BNP
antiproliferative agents that are inspired by BGCs which, until now, have remained hidden in the genomes of
cultured bacteria and metagenomes. Interestingly, nearly half of all drugs in clinical use today are inspired by
nonribosomal peptides (NRPs) or mixed polyketide-NRPs. Fortuitously, NRP biosynthesis is unique in that
bioinformatic algorithms have developed to the point where it is possible to predict many NRP structures from
primary data sequence alone. Concurrently with these bioinformatic advances, robust methods for synthetically
producing NRP-like structure have become simple and economical, making uncharacterized NRP BGCs model
targets for syn-BNP discovery studies and a potentially rich source of mechanistically diverse and novel
antiproliferative agents. With this in mind, in Aim 1 bioinformatic analysis of NRP BGCs found in publicly available
data bases will be used to inspire syn-BNPs that will be screened for differential antiproliferative activity across
a panel of diverse cancer lines. In Aim 2, metagenomic...

## Key facts

- **NIH application ID:** 10794401
- **Project number:** 5R01CA280019-02
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** SEAN F BRADY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $401,983
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10794401

## Citation

> US National Institutes of Health, RePORTER application 10794401, Discovery and characterization of synthetic bioinformatic natural product anticancer agents (5R01CA280019-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10794401. Licensed CC0.

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