# Studies to understand and exploit 10-membered enediyne biosynthesis

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $516,179

## Abstract

ABSTRACT
The 10-membered enediynes [exemplified by calicheamicin (CLM), esperamicin (ESP) and dynemicins (DYN)]
are arguably among the most renowned natural products (NPs) discovered to date by virtue of their
unprecedented complex molecular architectures, notable anticancer and anti-infective potencies and, in the case
of CLM, demonstrated clinical utility. The current study builds on a longstanding collaborative effort of
achievement and discovery relating to key aspects of 10-membered enediyne biosynthesis as well as parallel
innovative efforts to co-opt key biosynthetic catalysts for synthetic applications. The studies put forth will take
advantage of this strong foundation and a powerful combination of genetic, biochemical, chemical and protein
structural tools to elucidate the remaining unusual biosynthetic transformations and to exploit select catalysts for
enediyne non-native modification. Specifically, aims 1 and 2 will focus on extending our understanding of the
fundamental steps of enediyne core biosynthesis common to CLM/DYN/ESP, DYN anthraquinone biosynthesis
and a selected set of unique tailoring reactions (CLM/ESP thiosugar sulfur installation and aminopentose N-
alkylation, ESP C6-hydroxylation and O-glycosylation). In parallel, aim 3 will focus on tactical structural studies
to augment both aims 1 and 2 and the structural study of ‘unknowns’ to facilitate functional annotation. Additional
studies in aim 2 with key catalysts and corresponding non-native substrates are designed to assess the potential
for strategic installation of chemoselective handles to enable novel approaches for facile, mild bioconjugation of
CLM to tumor-targeting mAbs (in collaboration with Pfizer).

## Key facts

- **NIH application ID:** 9859206
- **Project number:** 5R01CA217255-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** GEORGE NEAL PHILLIPS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $516,179
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859206

## Citation

> US National Institutes of Health, RePORTER application 9859206, Studies to understand and exploit 10-membered enediyne biosynthesis (5R01CA217255-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9859206. Licensed CC0.

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