Abstract A43: Investigating novel inhibitors of the IMP-1-KRAS mRNA interaction
Bibliographic record
Abstract
Abstract K-Ras functionality is integral for cell growth and differentiation due its canonical role in signaling the PI3K and MAPK pathways. Genetic analysis on various cancers revealed that mutations in the K-Ras gene are responsible for 21% of all cases, which include lung, pancreatic and colorectal cancer. Prior efforts at directly targeting mutant K-Ras have been largely unsuccessful, thus creating a demand for novel therapeutic approaches. Common to the aforementioned cancers is expression of the Insulin-Like Growth Factor 2 mRNA Binding Protein 1 (IMP-1). IMP-1 is part of the VICKZ family of RNA-binding proteins known for post-transcriptional regulation, including its ability to shield its mRNA substrates from decay. One notable substrate of IMP-1 is the K-Ras mRNA, which was identified using UV-crosslinking experiments. Downregulation of IMP-1 through siRNA treatment led to a reduction of K-Ras protein by 60% in SW480 colorectal cancer cells and consequently reduced cell proliferation. The studies suggest a relationship between IMP-1 binding, mRNA turnover and the resultant protein expression of target substrates. To study the IMP-1-mRNA relationship and to help find inhibitors of such interaction, we developed a fluorescence polarization (FP) method that employed 45-nt K-Ras and 39-nt CD44 fluorescein-labeled RNA probes. Using full-length IMP1, truncated and point-mutated IMP1, we showed that the FP method faithfully recapitulated the relative affinity of recombinant proteins for both K-Ras and CD44 RNAs. The FP method was then used to find inhibitors of the IMP-1-K-Ras mRNA interaction and to elucidate potential domain target of inhibitors. We found that oligonucleotides SM6 and SM7, but not SM2, could significantly reduce the FP units, consistent with the results from electrophoretic mobility shift assay. In addition, the molecule UNBC143 was found to decrease FP units in a dose-dependent manner, suggesting its ability to inhibit IMP-1-K-Ras RNA interaction. The SM oligonucleotides and UNBC143 were also assessed on K-Ras expression in SW480 human colon cancer cells. These experiments and their results will be discussed in further detail upon presentation. Citation Format: Victor Liu, Chuyi Wang, Chow Lee. Investigating novel inhibitors of the IMP-1-KRAS mRNA interaction [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A43.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".