# A Unique Class of Reductively Activated Oncology Drugs

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $718,986

## Abstract

The design, synthesis, and evaluation of a unique class of reductively activated N-acyl O-aminophenol
prodrug analogues of the duocarmycins are investigated to ultimately improve cancer therapy. Studies
to date demonstrate that: (1) the N-acyl O-aminophenol prodrugs release the free drug in vitro providing
derivatives that approach the potency of the parent free drug, (2) this reactivity may be finely tuned by
changing both the electron-withdrawing character (reactivity: R = NHCOR > NHCO2R > NMeCO2R >
NHCONH2) and steric environment surrounding the amino group, (3) these reactivity differences translate
into a remarkable range of prodrug stabilities and propensities for N–O bond cleavage even with subtle
variations in the electronic and steric parameters, (4) there are clear predictable correlations between
ease of cleavage, in vitro cytotoxicity, and in vivo potency and efficacy, and (5) that those prodrugs which
exhibit a well-balanced reactivity [stability vs cleavage] also exhibit in vivo antitumor efficacies that greatly
surpass those of the parent drugs. Plans are detailed to: (1) examine additional N–O prodrug designs to
further define the structure-function properties, (2) analyze mechanism of in vitro and in vivo N–O bond
cleavage with free drug release, and (3) comprehensively examine the most promising and advanced
prodrug candidate prepared to date for its ability to inhibit progression of otherwise hard-to-treat cancers
in advanced preclinical models. These studies will refine an understanding of the prodrug's in vivo
behavior, provide a compelling rationale for its use in targeted therapy, and help define the tumor
indication and patient populations most likely to respond to drug administration. Displaying remarkable
stability in plasma, a therapeutic window of anti-tumor efficacy much larger than the free drug in a simple
tumor model, slow sustained free drug release and preferential free drug release in tumor tissue versus
plasma, combined with a stunning lack of bone marrow toxicity, the lead prodrug candidate will be
examined in models of aggressive breast cancer and advanced metastatic disease. Addressing the most
challenging unmet clinical needs, the lead prodrug will be further investigated in brain metastasis and
glioma, conditions that are generally fatal and very likely to benefit from the blood brain barrier penetrance
of our prodrug and its proposed ability to inhibit growth of otherwise drug-resistant cancer cells.
Information and therapeutic tools from this study will enrich the field, foster development of targeted highly
effective cancer drugs, and might directly enable clinical investigation of a unique new class of reductively
activated duocarmycin prodrugs with unparalleled efficacy and safety to provide treatment for cancer
patients with otherwise fatal conditions.

## Key facts

- **NIH application ID:** 9858292
- **Project number:** 5R01CA208669-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** DALE L BOGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $718,986
- **Award type:** 5
- **Project period:** 2017-03-14 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858292

## Citation

> US National Institutes of Health, RePORTER application 9858292, A Unique Class of Reductively Activated Oncology Drugs (5R01CA208669-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9858292. Licensed CC0.

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