# Development of Best-in-Class Pol-Theta Inhibitors

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2024 · $712,514

## Abstract

Project summary.
BRCA1 and BRCA2 facilitate DNA double-strand break (DSB) repair via homologous recombination (HR). Yet
BRCA1/2 are often mutated in cancers, such as breast/ovarian/prostate/pancreatic carcinomas. BRCA-deficient
cancer cells are therefore HR-defective, and susceptible to agents that induce DNA damage and/or prevent DSB
repair. For instance, Poly-ADP ribose polymerase 1 (PARP1) inhibitors (PARPi) preferentially kill BRCA-deficient
cancer cells and are approved to treat HR-deficient cancers. However, only ~60% patients respond to PARPi
and drug resistance is a major problem. Thus, developing second-generation precision medicines that target
HR-deficient cancers and/or overcome PARPi resistance is urgently needed.
 DNA polymerase theta (Polq), a DNA repair factor important for microhomology-mediated end-joining
(MMEJ) of DSBs, has been recently validated as a druggable target in BRCA-deficient cancers. Polq is essential
for BRCA-deficient cancer cells, but is dispensable for BRCA-proficient cells, and Polq null mice exhibit no major
phenotypes. Recently reported Polq inhibitors (Polqi) showed preferential killing of BRCA-deficient cells. Yet,
these early stage inhibitors have significant deficiencies (i.e. poor ADME and PK parameters, or low potency)
which may limit their efficacy in clinical studies. We have developed a novel, oral bioavailable Polqi that exhibits
5.1 nM IC50 against Polq polymerase (Polq-pol), selectively kills BRCA-deficient cells, and exhibits better
pharmacokinetics than recently published Polqi. Our collaborative team (Pomerantz, Johnson, and Childers labs)
plans to further improve and demonstrate proof-of-principle of our novel Polqi as the potentially best-in-class
Polqi by developing the following Aims: 1. Optimization of Polqi via a prodrug strategy; 2. Biochemical and
cellular characterization of Polqi; 3. In vivo efficacy of optimized Polqi in BRCA-deficient solid tumors.
We expect that successful completion of these Aims will enable the development of a potentially best-in-class
Polqi prodrug candidate.

## Key facts

- **NIH application ID:** 10882723
- **Project number:** 1R01CA283323-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Wayne E Childers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $712,514
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882723

## Citation

> US National Institutes of Health, RePORTER application 10882723, Development of Best-in-Class Pol-Theta Inhibitors (1R01CA283323-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10882723. Licensed CC0.

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