# Structure Based Design of Pol-theta inhibitors

> **NIH NIH R41** · RECOMBINATION THERAPEUTICS, LLC · 2021 · $385,900

## Abstract

Acute myeloid leukemia (AML) is the most frequently diagnosed form of acute leukemia in adults, and standard
of care treatment involving chemotherapy and/or stem cell transplantation only cures 30-40% of patients. Recent
studies show that AMLs with FLT3 receptor activating internal tandem duplication (ITD) mutations (FLT3(ITD)-
positive AMLs) become defective in the BRCA1/2 pathway of homologous recombination (HR) following
treatment with tyrosine kinase inhibitors (TKi). BRCA-deficiency confers strong sensitivity to DNA damage and/or
DNA repair inhibition, and thus presents a promising new therapeutic strategy for AML. We discovered that
BRCA-deficient leukemia cells are hyper-dependent on the DNA repair enzyme DNA polymerase theta
(Polθ), which is dispensable for normal cells and mice. Polθ is involved in translesion synthesis and the
microhomology-mediated end-joining (MMEJ) double-strand break (DSB) repair pathway. Our leading small-
molecule Polθ inhibitor (Polθi) kills AML patient cells co-treated with the TKi quizartinib which causes
BRCA-deficiency, whereas quizartinib and Polθi as single agents shows significantly less killing. These
data demonstrate the Polθi + TKi combination as a promising therapeutic strategy for FLT3(ITD)-positive AML.
Polθi also shows preferential killing of other BRCA-deficient leukemias (ALL, CML) in vitro and in vivo, especially
in combination with TKi. In summary, our data discover Polθ as a novel drug target in leukemia, and demonstrate
Polθi + TKi as a promising therapeutic strategy, especially in aggressive FLT3(ITD)-positive AML. In phase I,
Recombination Therapeutics, LLC (RTx), a start-up precision oncology company, plans to increase the potency
of our leading Polθi as a novel treatment for FLT3(IDT)-positive AML using X-ray crystallography and structure
based optimization/design by developing the following Aims: 1. To solve the co-crystal structure of Polθ-DNA-
Polθi ternary complexes; 2. To optimize Polθi using structure based optimization/design.
 In Phase II, RTx aims to achieve the following goals: 1. Further develop our leading Polθi drug candidate
by achieving more favorable ADME and pharmacokinetic parameters; 2. Characterize optimized Polθi in
combination with TKi in FLT3(IDT)-positive AML animal models in vivo.

## Key facts

- **NIH application ID:** 10323627
- **Project number:** 1R41CA265430-01
- **Recipient organization:** RECOMBINATION THERAPEUTICS, LLC
- **Principal Investigator:** Richard T Pomerantz
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,900
- **Award type:** 1
- **Project period:** 2021-07-16 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10323627

## Citation

> US National Institutes of Health, RePORTER application 10323627, Structure Based Design of Pol-theta inhibitors (1R41CA265430-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10323627. Licensed CC0.

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