# Biosynthesis of the Leinamycin Family of Natural Products: Mechanistic Studies and Chemoenzymatic Analog Synthesis

> **NIH NIH F32** · SCRIPPS FLORIDA · 2021 · $60,695

## Abstract

PROJECT SUMMARY/ABSTRACT
 Chemotherapy has been the centerpiece of cancer treatment in modern society, and will remain so for
the foreseeable future. DNA-damaging compounds have seen the most use historically in this regard, due to
cancer cells’ increased rates of growth and proliferation relative to normal, healthy cells. However, these
treatments often cause off-target effects and resistance development. Therefore, compounds that can damage
cancer cell DNA in a selective fashion and with a mechanism complementary to current clinical treatments
offer solutions to both of these issues. The natural product leinamycin (LNM) is a DNA-damaging compound
that only elicits its DNA-damaging effects upon activation by thiols, and has nanomolar activity against tumor
cells resistant to clinically utilized drugs. LNM E1 is an engineered LNM analog that upon activation by reactive
oxygen species (ROS) exerts its antitumor activity via a mechanism orthogonal to LNM. A single scaffold that
can be primed for DNA damage in two complementary ways is unique to this set of compounds, and sets the
stage for further optimization of the LNM scaffold in terms of anticancer activity. The biosynthetic origin of LNM
in Streptomyces has been an area of intense study, and many of the biosynthetic steps have been elucidated
and led to discoveries involving unprecedented chemical steps. The long-term goals of this project are to
harness the power of a mechanistic understanding of LNM biosynthesis to genetically alter producing
organisms for production of analogs with improved therapeutic properties. This proposal contains two aims: (i)
investigate the mechanism of a key biosynthetic step and (ii) access rationally-designed analogs of both LNM
and LNM E1 to answer specific questions about the compounds’ biological activities. The central hypothesis of
this proposal is that LNM compounds can be tuned and improved in both stability and potency through rational
design. This hypothesis is rationalized by Nature’s ability to produce an array of LNM-type compounds, which
have served as the inspiration for the structural changes proposed herein. The outcomes of this application will
be a mechanistic understanding of one of the key steps of LNM biosynthesis and access to novel LNM analogs
that can be used to answer key questions about LNM DNA-damaging and anticancer activity. These findings
can be applied to the long-term goal of rational biosynthetic manipulation to produce targeted structural LNM
analogs for further anticancer development.

## Key facts

- **NIH application ID:** 10136030
- **Project number:** 5F32GM133114-03
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Andrew Steele
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $60,695
- **Award type:** 5
- **Project period:** 2019-05-16 → 2022-04-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136030

## Citation

> US National Institutes of Health, RePORTER application 10136030, Biosynthesis of the Leinamycin Family of Natural Products: Mechanistic Studies and Chemoenzymatic Analog Synthesis (5F32GM133114-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10136030. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*