Insight into the biological activity of a naturally-derived dithiopyrrolone with a wide spectrum activity against metastatic cancer models
Bibliographic record
Abstract
LB-325 Mortality from cancer is attributed primarily to the dissemination of primary tumor cells to distant organs, where only limited therapeutic options are available for patients. The newly introduced targeted therapies for metastatic cancer such as trastuzumab have provided encouraging clinical results and reinforced the effectiveness of targeting cancer-associated targets. However, only small subgroups of patients benefit from targeted agents due to the common heterogeneity in target expression and the occurrence of relapses. There is continued drive to identify antimetastatic agents with polyfunctional mechanisms. Here, we report preclinical and biochemical data on a novel molecule (WBI-2100) with structural features that are distinct from those of other anti-cancer agents, and with activity against advanced preclinical cancer models resistant to many chemotherapy drugs and targeted agents. WBI-2100 is an N-aryl-5-alkylidene-2,5-dihydropyrrol-2-dithiopyrrolone initially isolated from the symbiotic microorganism, Xenorhabdus spp., and further optimized through chemical synthesis. WBI-2100 is a highly tolerated molecule, even after long-term, chronic administration, and displays an excellent biodistribution when administered by intraperitoneal or by oral route to mouse preclinical models. Antitumor activity was seen in melanoma, breast, and liver human xenografts following either intraperitoneal or oral administration. Interestingly, WBI-2100 shows also antimetastatic activity in a human breast cancer model that is highly invasive when implanted into the mammary fat pad of mice, as well as in two rodent metastatic models, e.g. lung Lewis carcinoma and B16-BL6 models. In combination treatment, WBI-2100 showed a superior activity when combined with the chemotherapeutic drugs taxol, dacarbazine, and cisplatin. Biochemical studies have demonstrated that WBI-2100 has potent anti-invasive activity in the Boyden chamber assay and antiangiogenic activity in tube formation and in in vivo matrigel-plug assays, and with its selective induction of apoptosis in human endothelial cells at concentrations that are less toxic to cancer cells. Ongoing molecular and structural studies are dissecting the molecular target(s) for this molecule. In summary, we report a novel naturally-derived small molecule with anti-cancer properties that support a potential clinical utility for advanced human cancer.
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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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".