Assessing the Binding Affinity of a Small Molecule for the c-Myc oncogene guanine quadruplex for targeted anticancer applications
Bibliographic record
Abstract
Cancer is a group of diseases defined by abnormal cell growth that can invade different tissues and is caused by mutations to certain genes leading to uncontrolled cellular proliferation.[1] Found in all cells, deoxyribonucleic acid (DNA) encodes through five bases the genes needed to make every protein in the body. Aside from its conventional double helical structure, DNA can form higher-order architectures called guanine quadruplexes (G4s). G4s are composed of planar tetrads of four hydrogen-bonded guanines stabilized by a central cation that help limit the expression of cancer-related genes (Figure 1).[2] c-Myc is a gene that is overexpressed in the majority of human cancers.[3] Overexpression of c-Myc upregulates cellular growth and metabolism pathways central to cancer.[3] The region of the c-Myc gene that controls its expression (‘promoter region’) can fold into a G4.[4] Enforcing the folding of the c-Myc promoter into a G4 using small molecules can prevent c-Myc expression leading to cancer. Two years ago, the Petitjean Group made an exciting discovery of a binder which showed uniquely high affinity for G4s, while not associating with duplex DNA.[5] In my research presented here, I am using the fluorescence indicator displacement assay to indirectly assess binding constants and determine the degree of stabilization this binder offered to the c-Myc G4. Knowing the stabilization offered by this binder to c-Myc G4 can allow further research into a second generation of binders for targeted anticancer applications. Figure 1. Planar tetrads of hydrogen-bonded guanines (left) stacked to form a G4 (right). G4-selective binder (yellow). References [1] Miller, D. M.; Thomas, S. D.; Islam, A.; Muench, D.; Sedoris, K. Clin. Canc. Res. 2013, 18, 5546-5553. [2] Ruggiero, E.; Richter, S. N. Nucleic Acids Res. 2018, 46, 3270-3283. [3] Brooks, T. A.; Hurley, L. H. Genes Cancer. 2010, 6, 641-649. [4] You, H.; Wu, J.; Shao, F.; Yan, J. J. Am. Chem. Soc. 2015, 7, 2424-2427. [5] a) Caitlin E. Miron, PhD Thesis, Queen’s University, 2018; b) C. E. Miron, J.-L. Mergny, A. Petitjean, Platinum Compounds for Binding Guanine Quadruplexes, PCT/C2018/051399.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".