Abstract 4289: Discovery of potent RAD51 inhibitors with anticancer activity in preclinical models of non-small cell lung cancer
Bibliographic record
Abstract
RAD51 is a protein that plays a key, canonical role in double-strand break (DSB) repair through homologous recombination (HR) and is biologically important for maintaining genome stability. Given its additional, non-canonical role in mitigating the replication stress characteristic of tumor cells, RAD51 has emerged as an attractive therapeutic target in several malignancies including non-small cell lung cancer (NSCLC). Nonetheless, drug discovery endeavors for developing direct RAD51 inhibitors have had limited success. Here, we describe a series of novel RAD51 inhibitors and their cytotoxic activity in preclinical models of NSCLC. We accessed and improved upon a previously discovered series of phenylsulfonyl indolyl isoquinoline derivatives that bind to the hydrophobic pocket of RAD51 preventing its multimerization and interaction with BRCA2. Of these, JKYN-1 and its mesylate salt (patent application # CA3204011A1) displayed potent and selective RAD51 inhibition in cell-free assays. Given the biological importance of replication stress in a subset of NSCLC, we assessed the cytotoxicity of these RAD51 inhibitors in preclinical models of NSCLC. Using the CellTiter-Glo assay, JKYN-1 displayed cytotoxicity in A549 and H1975 cell lines with lower IC50 values compared to the classical RAD51 inhibitor B02 (A549, 4.9 vs >10 μM; H1975, 3.2 vs 8.3 μM). We subsequently assessed the cytotoxicity in a panel of 7 patient-derived organoids (PDOs) of NSCLC with diverse molecular, genetic, and clinical profiles (LPTO308, XDO137, LPTO357, LPTO318, LPTO366, LPTO362, LPTO221). In these models, JKYN-1 and JKYN-1-mesylate displayed a highly potent cytotoxicity with sub-micromolar IC50 values between 0.1-0.87 μM as opposed to B02 that had IC50 values between 3.7 to >10 μM. In conclusion, our data identify JKYN-1 and its mesylate salt as potent and selective RAD51 inhibitors with superior cytotoxic activity compared to classical inhibitors such as B02. These findings highlight the potential of these novel compounds as promising therapeutic agents in a subset of NSCLC. Citation Format: Yifan Yu, Morgan Black, Nikolina Radulovich, Peter Ferguson, James Koropatnick, Ming Tsao, Mark D. Vincent, Geoffrey Liu, Samir H. Barghout. Discovery of potent RAD51 inhibitors with anticancer activity in preclinical models of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4289.
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 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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| 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".