Abstract B25: “TargetDBR”—A DNA repair drug and target discovery collaboration: Exploiting synthetic lethal, high content, and functional cellular reporter assays to accelerate DNA repair targeted drug discovery
Bibliographic record
Abstract
Abstract Most cancer therapies involve a component of treatment that inflicts DNA damage in tumor cells, such as double-strand breaks (DSBs), which are considered the most serious threat to genomic integrity. Inhibition of DSB repair sensitizes cells to these therapies. Mutations have been reported in nearly every DNA repair pathway and these pathways often exhibit redundancy. Inhibition of functional repair factors can induce synthetic lethality in repair-deficient tumors even in the absence of exogenous DNA damage and whilst sparing healthy tissue. We demonstrate a compound and target discovery platform comprising the integration of isogenic cell line screening, high content repair foci assays and relative DSB repair pathway reporting cells, along with chemical biology and medicinal chemistry. Two diverse drug-like compound library screens have been conducted. Screening for synthetic lethality with deficiency in FANCD2 and BRCA2 led to a hit series broadly active against a range of homologous recombination (HR) repair deficiencies, which is now undergoing medicinal chemistry optimization and target deconvolution studies. Outcome of these initial chemoproteomic target pulldown experiments will be presented. A second cellular screen, (50k compounds) for inhibition of BRCA1 and Rad51 foci formation following radiomimetic drug induced DNA damage, has led to identification of compounds that inhibit damage response after ionizing radiation and selectively inhibit HR repair. Focusing on therapeutic targeting of proliferating tumor cells, our research platform has enabled novel hit compound identification, mechanistic profiling, hit-to-lead optimization chemistry and proof of concept efficacy in in vitro tumor models. Effects on tumor cell clonogenic survival and sensitization towards chemotherapeutics and ionizing radiation will be presented, along with comparisons to known DNA repair inhibitors that demonstrate these compounds' differentiated mechanisms of action. TargetDBR has created a technology platform focused on DNA repair inhibitor discovery and has identified differentiated hits and lead series with potential for development and opportunity to meet the need for new druggable targets in oncology. Citation Format: Jonathan J. Hollick, Laura Abriola, Francoise Bono, Denise Hegan, Pamela Klingbeil, Yanfeng Liu, Ranjini Sundaram, Yulia V. Surovtseva, Mark Whittaker, Ranjit S. Bindra, Peter M. Glazer. “TargetDBR”—A DNA repair drug and target discovery collaboration: Exploiting synthetic lethal, high content, and functional cellular reporter assays to accelerate DNA repair targeted drug discovery [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B25.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| 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".