Abstract PO-039: Antiproliferative activity of inhibitors of RAD51, singly and in combination with chemotherapy drugs, against pancreatic cancer cell lines
Bibliographic record
Abstract
Abstract Despite the innovations in chemotherapeutic treatment of pancreatic cancer, the generally poor outcome of this disease begs the search for novel targets. RAD51 is a critical component of homologous recombination DNA repair, binding with BRCA2 and forming polymeric filaments essential for its function. RAD51 is often elevated in cancer cells compared to normal cells, particularly in pancreatic cancer: RAD51 is a negative prognostic biomarker and promotes tumor cell proliferation in that disease (Cancer Cell Int 19: 356, 2019; doi: 10.1186/s12935-019-1077-6). Therefore, RAD51 is an attractive target for anticancer treatment in that its elevated level and activity in tumor cells provide a potential level of selectivity for such an agent, increasing the therapeutic index. We demonstrated previously that novel inhibitors of RAD51, IBR2 [2-(Benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline] and IBR120 (an isoindolinyl derivative of IBR2) (Eur J Med Chem. 96:196-208, 2015; doi: 10.1016/j.ejmech.2015.04.021), not only inhibited proliferation of a range of tumor cell lines at micromolar concentrations but also acted in combination with commonly used cytotoxic chemotherapy and molecularly targeted drugs to synergistically inhibit proliferation (J Pharmacol Expt Ther, 364: 46-54, 2018; doi.org/10.1124/jpet.117.241661). To improve ADME properties, enhance activity, and increase potential to selectively target RAD51, advanced computational tools and rational approaches were employed to predict possible modification to the IBR chemical backbone. This effort resulted in discovery of the compound JKYN-1. As a model system in which to test the activity of JKYN-1 in vitro, human pancreatic cancer cell lines PANC-1, Capan-1 and Capan-2 were used. All lines have mutant K-Ras and p53, and Capan-1 has mutant BRCA2 (https://www.cancer.gov/research/key-initiatives/ras; https://web.expasy.org/cellosaurus). JKYN-1 or its water-soluble methylsulfonate salt (JKYN-1-mesylate) inhibit proliferation of PANC-1 cells approximately 5 times more effectively than IBR120 and inhibit Capan-1 and Capan-2 cells even better. Against PANC-1, JKYN-1-mesylate inhibits proliferation synergistically in combination with afatinib (inhibitor of epidermal growth factor receptor) or with IBR120, and is additive with gemcitabine. Biochemical characterization of the interaction between RAD51 and these inhibitors demonstrated the following: (1) IBR2 and IBR120 promote disassembly of RAD51 multimers in an ex vivo native polyacrylamide gel electrophoresis assay using clonal constructs of RAD51, and (2) JKYN-1 binds to RAD51 with higher affinity than IBR120 and B02, a commercially available RAD51 inhibitor, in a surface plasmon resonance spectroscopy assay. Therefore, JKYN-1 is a potential novel small molecule therapeutic agent for treatment of pancreatic cancer, both as a single agent and in combination with standard chemotherapy drugs. Citation Format: Peter Ferguson, Mark D. Vincent, Yousef Najajreh, Brian Shilton, Stephen Ritter, Rima Al-awar, Richard Marcellus, Mohammed Mohammed, Methvin Isaac, James Koropatnnick. Antiproliferative activity of inhibitors of RAD51, singly and in combination with chemotherapy drugs, against pancreatic cancer cell lines [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-039.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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) | 0.006 | 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".