Abstract A25: COTI-2, a novel small molecule that is effective against multiple human cancer cell lines in vitro and in vivo
Bibliographic record
Abstract
Abstract Introduction: Identification of novel anti-cancer compounds with high efficacy and low toxicity is critical in drug development. High-throughput screening and other such strategies are generally resource-intensive. Therefore, in silico computer-aided drug design has gained rapid acceptance and popularity. We employed our proprietary computational platform (CHEMSAS®), which uses a unique combination of traditional and modern pharmacology principles, statistical modeling, medicinal chemistry, and machine-learning technologies to discover and optimize novel compounds that could target various cancers. COTI-2 is a novel, small molecule, candidate anti-cancer drug identified using CHEMSAS. This study describes the in vitro and in vivo evaluation of COTI-2. Methods: A series of cell proliferation and cell viability assays including alamarBlue®, cell counting, CellTiter-Blue®, and flow cytometry were used to measure the effect of COTI-2 on tumor cell proliferation and apoptosis in a wide range of human cancer cell lines. COTI-2 was also tested in vivo against several human xenograft models. Two independent kinase assays were used to examine whether COTI-2 is a kinase inhibitor. The capacity of COTI-2 to inhibit Hsp90 was determined using an Hsp90 ATPase activity assay. A series of knockdown studies of the PI3K/AKTmTOR pathway were used to evaluate the effect of COTI-2 on this pathway. Finally, the effect of COTI-2 on mutant p53 was evaluated using p53 conformational studies. Results: Our data demonstrate that COTI-2 is effective against a diverse group of human cancer cell lines regardless of their tissue of origin or genetic makeup. Most treated cancer cell lines were sensitive to COTI-2 at nanomolar concentrations. When compared to traditional chemotherapy or targeted-therapy agents, COTI-2 showed superior activity against tumor cells, in vitro and in vivo. Despite its potent anti-tumor efficacy, COTI-2 was safe and well-tolerated in mouse hosts of human tumor xenografts in vivo. Our preliminary mechanism of action results indicate that COTI-2 is not a traditional kinase or an Hsp90 inhibitor but that AKT and p53 are likely targets of COTI-2. Conclusion: COTI-2 is a novel, anti-cancer agent that was designed by our proprietary computational platform CHEMSAS. It is effective against a wide variety of human cancer cell lines in vitro and in vivo, regardless of their tissue of origin or genetic make-up. COTI-2 induces apoptosis in tumor cells in vitro, is well-tolerated in vivo, and does not cause toxicity in treated animals. COTI-2 is not a traditional kinase or Hsp90 inhibitor. Finally, COTI-2 appears to target mutant p53 and the PI3K/AKT/mTOR pathway. Citation Format: Kowthar Y. Salim, Saman Maleki Vareki, Wayne R. Danter, James Koropatnick. COTI-2, a novel small molecule that is effective against multiple human cancer cell lines in vitro and in vivo. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A25.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| 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".