G4 Binders As Potent Selective Transcription Inhibitors

Qualigen licensed the G4 selective transcription inhibitor platform from University College London (UCL) in 2022. The licensed technology comprises lead compound QN-302 (formerly SOP1812) and back-up compounds that target regulatory regions of cancer genes that down-regulate gene expression in multiple cancer pathways. Developed by Dr. Stephen Neidle and his group at UCL, the G4 binding concept is derived from 30+ years in nucleic acid research, including that of G4s, which are higher order DNA and RNA structures formed by sequences containing guanine-rich repeats. G4s are overrepresented in telomeres as well as promoter sequences and untranslated regions of many oncogenes. Their prevalence is therefore significantly greater in cancer cells compared to normal human cells1.

G4-selective small molecules such as QN-302 and backup compounds target the regulatory regions of those cancer genes which have a high prevalence of enriched G4s in a process that can be predicted by bioinformatics. Stable G4-QN-302 complexes can be impediments to replication, transcription or translation of those cancer genes containing G4s, and the drugs’ binding to G4s stabilize the G4s against possible “unwinding.” G4 binders like QN-302 could be efficacious in a variety of cancer types with a high prevalence of G4s such as PDAC (Pancreatic Ductal Adenocarcinoma), prostate, sarcomas, and GIST (Gastrointestinal Stromal Tumors).

High Affinity G4 Binder QN-302 as Treatment for Pancreatic Cancer

Pancreatic cancer is the tenth most common cancer and fifth deadliest in the United States and has one of the lowest rates of survival of all cancer types, with 98% of those diagnosed dying from the disease and one in four dying within the first month of diagnosis. The chemotherapy drug gemcitabine has been standard of care for patients with metastatic pancreatic cancer for more than 15 years. Numerous clinical trials have tested new drugs, either alone or in combination, with gemcitabine. QN-302 is potentially a first-in-class small molecule drug candidate with superior efficacy and activity against pancreatic cancer compared to existing agents, with a distinct mechanism of action and preclinical target profile.

In-vitro and in-vivo studies have shown that G4 stabilization by the G4 selective small molecule QN-302 result in inhibition of target gene expression and cessation of cell growth in a variety of cancers, including pancreatic ductal adenocarcinoma (“PDAC”) which represents 98% of pancreatic cancers. To start, QN-302 potently inhibits the growth of several PDAC cell lines at low nM concentrations. Likewise, QN-302 shows longer survival duration in a KPC genetic mouse model for pancreatic cancer than gemcitabine has historically shown. Additional preclinical studies suggest activity in gemcitabine resistant PDAC. Data from therapy studies on three patient-derived PDAC xenografts further demonstrates that QN-302 has significant anti-tumor activity in PDAC. Early safety indicators suggest no adverse toxic effects at proposed therapeutic doses in pancreatic cancer in-vivo models.

Potential Advantages

  1. Granted ODD (Orphan Drug Designation) for pancreatic cancer
  2. Composition of matter IP protection covering QN-302 and back-up compounds
  3. QN-302 is a small molecule with straightforward four-step synthesis
  4. Evidence for high affinity G4 target engagement
  5. Nanomolar anti-proliferative activity in variety of cancer cell lines, including MIA-PACA2 cells
  6. Anti-tumor activity in-vivo in multiple pancreatic cancer models, including PDx models
  7. Long half-lives (>24hrs) and favorable in vivo exposure
  8. No adverse toxic effects in-vivo at proposed therapeutic doses
  9. No significant adverse effects on blood chemistry in pancreatic cancer in-vivo model
  10. Potential efficacy against GIST (Gastrointestinal Stroma Tumors) and promising in-vivo activity against hormone-resistant prostate cancer
  11. Potential for multiple cancer indications and Orphan Drug designations

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  1. Hänsel-Hertsch R et al. G-quadruplex structures mark human regulatory chromatin. Nat Genet. 2016 Oct;48(10):1267-72. doi: 10.1038/ng.3662. Epub 2016 Sep 12. PMID: 27618450.
  2. “Combination of Nab-Paclitaxel and Gemcitabine Improves Survival in Patients with Metastatic Pancreatic Cancer.” www.cancer.gov/types/pancreatic/research/nab-paclitaxel-gemcitabine
  3. Ahmed A et al. Asymmetrically Substituted Quadruplex-Binding Naphthalene Diimide Showing Potent Activity in Pancreatic Cancer Models. ACS Med Chem Lett. 2020 Jul 16;11(8):1634-1644. doi: 10.1021/acsmedchemlett.0c00317
  4. Ahmed et al. A G-quadruplex-binding compound shows potent activity in human gemcitabine-resistant pancreatic cancer cells. Sci Rep. 2020 Jul 22;10(1):12192. doi: 10.1038/s41598-020-68944-w.