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ABLeS Participant Computational Drug Discovery Biology Group

Project title

Utilising splicing modulator induced poison exons as a therapy for high-risk AML

Collaborators and funding

  • Children’s Cancer Institute, The Druggable Transcriptome: Small Molecules Inducing Reading Frame Shifts (SMIRFS) $1,313,681

  • NHMRC Ideas Grant (01 Jan 2025 - 31 Dec 2027), CIA, Treating Childhood Cancers by Small Molecule Mediated Reactivation of Tumour Suppressors $500,000

  • Luminesce Alliance (01 Jul 2025 - 30 Jun 2027), CIA, Paralog-sparing targeting of H3-3A, the carrier of Diffuse Midline Glioma’s founding driver mutation H3K27M £242,997

  • CRUK Catalyst Grant (01 Nov 2025 - 31 May 2027), CIA, Critical validation of our proprietary RNA splicing modulation discovery platform $25,000

  • CCI Seed Fund (01 Jun 2025 - 31 May 2026), CIB, Exploring a Novel Alpha-Synuclein Isoform for Therapeutic Control of Its Expression in Parkinson’s Disease Induced Pluripotent Stem Cells £19,800

  • Rosetrees / Seedcorn (01 Oct 2025 - 31 Sept 2026), CIB, The ACRF Childhood Cancer Early Detection, Prevention and Treatment (ACCEPT) Program $5,500,000

  • ACRF (01 Feb 2025 - 31 Jan 2032), CIJ

Contact(s)

Project description and aims

Overview: This project will characterize the splicing effect of known splicing modulators on AML with splicing mutations (Aim1, transcriptomics). Next, we will generate (Aim2, medicinal chemistry) then characterize (Aim3, transcriptomics) novel related splicing modulator compounds with the most therapeutically promising ‘poison’ inclusion for synthetic lethal therapy in AML.

  • Aim 1: Characterize known splicing modulators impact on AML with spliceosomal mutations. Known splicing modulators introduce splicing events specific to AML, due to their spliceosomal mutations. Through transcriptomics analysis (RNAseq & dFORCE) of cell lines with and without spliceosomal mutation, we can prioritize which splicing event to pursue for medicinal chemistry optimization. To do so we will use AML cell lines with and without splice mutations, and treat both conditions with Branaplam, Risdiplam and Votoplam. RNA-seq will provide a deep transcriptome wide assessment of splicing events, while dFORCE (https://doi.org/10.1101/2025.04.27.650906) will provide single-molecule long-read assessment of treatment.
  • Aim 2: Generate novel compounds related to known splicing modulators Branaplam, Risdiplam and Votoplam are structurally similar. Nonetheless they introduce different splicing effects. A panel of ~20 structural analogues will be synthesized to investigate how structure affects splicing. In addition to completely novel structures, we will also survey existing literature/patents for interesting compounds. For instance, although compounds in the Branaplam patent may be weak splicing modulators of the intended target SMN2, they may strongly affect AML specific splicing events.
  • Aim 3: Identify the most promising new compound for splice-mutant AML In this aim we will expand the characterization presented in Aim1 to the novel compounds generated in Aim2. By using the pioneering dFORCE technology in addition to RNAseq, we will generate the deepest characterization globally of splicing modulators. This new knowledge will identify which structures and compounds bias towards AML specific events. Expected Outcome: We will identify compounds representing precursor drugs ready for chemical optimization, preclinical development, and eventually full clinical development.

How is ABLeS supporting this work?

This work is supported through the Production Bioinformatics scheme provided by ABLeS.

Expected outputs enabled by participation in ABLeS

We expect our analysis to show that the novel analogs induce deleterious, cancer-specific splicing alterations, opening a new therapeutic strategy for hard-to-treat cancers such as AML.


These details have been provided by project members at project initiation. For more information on the project, please consult the contact(s) or project links above.