Race Oncology: Bisantrene’s Primary MOA Identified as G-Quadruplex (G4) Binding - Anti-Cancer Narrative
- Noel Ong
- Oct 21
- 6 min read
Announcement
Race Oncology Limited (ASX: RAC) has reported a pivotal mechanistic discovery: its lead molecule (E,E)-bisantrene (RCDS1) (Figure 1) primarily exerts anticancer activity by binding and stabilising G-quadruplex (G4) structures in DNA and RNA—not via an anthracycline-like pathway. The Company positions this as a step-change for clinical strategy, biomarker development, and partnering.
Figure 1: (E,E)-Bisantrene – Chemical Structure (source: RAC)
Bisantrene – Chemical Struct
Key Highlights - An Anti-Cancer Story
1. Primary MOA redefined: RCDS1 binds and stabilises G4 DNA/RNA structures that regulate oncogene expression, including the master regulator MYC (Figure 2). This differentiates RCDS1 from doxorubicin-like chemotherapeutics.
Figure 2: Model of RCDS1 (E,E-bisantrene) binding to the G4 DNA structure found within the promoter region of MYC. (source: RAC)
2. Mechanistic clustering: Across 102 cancer cell lines and 195 drugs, RCDS1 clustered with G4-binding agents (e.g., actinomycin D), not with anthracyclines (Figure 3).
Figure 3: Cluster analysis of the anticancer responses of 195 drugs across 102 cancer cell lines showing that RCDS1 (E,Ebisantrene) is similar in mechanism of action to the G4-DNA binding drug actinomycin D. (source: RAC)
3. Downstream effects consistent with G4 binding (Figure 4):
• Inhibition of topoisomerase II and telomerase
• Reduction in activity of oncogenes (e.g., MYC, c-KIT, KRAS, TERT, EGFR, BCL2, VEGF, HIF1A, MYB, PDGFA)
• Indirect increase in m6A RNA levels (via MYC/FTO/ALKBH5 axis and G4-RNA effects on METTL3/METTL14). These collectively support anticancer efficacy and resistance modification.
Figure 4: Binding of RCDS1 to G4-DNA and RNA structures causes multiple downstream anticancer effects. (source: RAC)
Context on MYC: MYC is overexpressed/dysregulated in ~70% of cancers and remains historically “undruggable”; G4-promoter targeting offers an indirect route to dampen MYC signalling (Figure 5).
Figure 5: Ligand binding to the MYC gene G4 promoter region causes a downregulation of MYC expression, resulting in reduced oncogenic signalling, cancer growth and anticancer therapy resistance. (source: RAC)
5. Direct MYC signal: Race reports dose-dependent downregulation of MYC shortly after RCDS1 treatment (example shown in MDA-MB-231 cells; EC50 ~322.5 nM) (Figure 6).
Figure 6: Expression of the MYC gene is dose-dependently downregulated by RCDS1 in MDA-MB-231 breast cancer cells. (source: RAC)
6. Clinical & commercial implications:
• Better indication selection and rational combinations
• Biomarker development to predict responders (MOA-linked pharmacodynamics)
• Stronger regulatory submissions (mechanism-informed)
• Improved partnering probability with large pharma.
7. Operational update: Race hosted a webinar on Wednesday, 8 October 2025 at 6 pm AEST to explain the discovery.
8. m6A RNA regulation schematic: m6A is a reader-mediated RNA mark that tunes splicing, export, translation, and mRNA stability (Figure 7).
Figure 7: Levels of m6A in RNA provide multifaceted regulation of gene expression. m6A levels affect transcription, alternative splicing, alternative polyadenylation, nuclear export, cap-dependent and cap-independent translation, mRNA degradation, and mRNA stabilisation. A diverse set of reader proteins that selectively bind m6A, either directly or indirectly, mediate the many effects on gene expression. (source: RAC)
Race Oncology CEO and Managing Director, Dr Daniel Tillett, commented:
“The discovery (E,E)-bisantrene acts primarily by binding to G4-DNA and RNA structures, and not like the chemotherapeutic doxorubicin, fundamentally changes our thinking on how to best use this drug in the clinic. Bisantrene continues to surprise, and we look forward to building on this mechanism of action discovery in our future clinical and commercial plans.”
What Changed & Why It Matters
Historically, bisantrene was assumed to function like anthracyclines based on early-era data; modern profiling and literature-guided experiments redirected the hypothesis to G4 targeting. This updated MOA explains clinical observations (e.g., differing toxicity profile) and gives Race a mechanism-anchored roadmap for: selecting tumour sub-types, designing combinations (including with doxorubicin for anticancer plus cardioprotection aims), and building predictive biomarkers.
Next Steps
Extend preclinical work on G4-DNA/RNA binding, efficacy, and resistance pathways.
Prioritise cancer indications and rational drug combinations for clinical testing.
Define commercial market opportunities and required clinical trials.
Publish MOA studies (journals/conferences).
Investor webinar: 8 Oct 2025, 6 pm AEST (registration link in announcement).
Samso Concluding Comments
This is a reframing of the bisantrene story. Moving from an assumed anthracycline-like profile to a G-quadruplex–first MOA, with downstream m6A effects and a clear link to MYC biology, gives Race a sharper scientific narrative and a cleaner line of sight to indication selection. Mechanism clarity does not de-risk everything—but it does reduce ambiguity around why and where the drug should work.
According to Race Oncology, a G4/MYC thesis naturally prioritises tumour settings where MYC programs are active and measurable, and it encourages combinations that exploit transcriptional stress or RNA metabolism. The m6A/reader engagement provides practical pharmacodynamic hooks that can be built into early trials—allowing faster “learn-and-kill” cycles rather than long, unfocused studies.
As one takes a look at the share price chart for RAC, there is no doubt that the market is now embracing the approval and "acceptance" path for the Race story. Is this the start of a larger pricing movement? One will have to DYOR and compare similar stories that have come before Race Oncology.
Samso has been covering the Race story for a while now, and it is exciting to see the near quadrupling of its market value over that time. As always, do your own work. I think that if Race can link this MOA to clean clinical signals and a credible path to registration, the equity story strengthens materially. Having a real solution in the anti-cancer arena is definitely worth more than the current market capitalisation of Race at AUD $746M
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