# Synthetic Biology for Splice Modulating Polyketides

> **NIH NIH R43** · VARIGEN BIOSCIENCES CORPORATION · 2024 · $297,088

## Abstract

Project Summary. Natural product-derived RNA splice modulators are being developed for the treatment of
acute myeloid leukemia as well as other cancers. As natural products with complex molecular architectures,
analogue synthesis, evaluation, and production scale up have proven challenging. Here we utilize the tools of
synthetic biology as a platform to synthesize complex polyketide splice modulators. The most established set of
splice modulators share a common mode of action targeting the SF3B multi-protein component within the U2-
snRNP of the spliceosome. They also share a common motif comprised of two functional moieties united through
a central diene. Combining the molecular diversity provided by medicinal chemistry with the flexibility and the
ability to scale metabolite production using synthetic biology, we will produce 17S-FD-895, a highly potent, in
vivo active lead for AML. This will overcome the chemical production bottleneck that is preventing this life saving
compound from reaching clinical trials. From this medicinal synthetic biology approach, we will identify a
promising production candidate that has the pre-clinical credentials to be further developed as a novel anticancer
therapeutic.

## Key facts

- **NIH application ID:** 10920004
- **Project number:** 1R43CA287469-01A1
- **Recipient organization:** VARIGEN BIOSCIENCES CORPORATION
- **Principal Investigator:** Michael D. Burkart
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $297,088
- **Award type:** 1
- **Project period:** 2024-07-01 → 2025-07-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10920004

## Citation

> US National Institutes of Health, RePORTER application 10920004, Synthetic Biology for Splice Modulating Polyketides (1R43CA287469-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10920004. Licensed CC0.

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