Abstract 5731: Structure-based development of a novel MYC inhibitor for neuroendocrine prostate cancer
Bibliographic record
Abstract
Abstract Background: MYC oncoproteins are important drivers of human cancers. More specifically, NMYC is amplified and overexpressed in neuroendocrine prostate cancer (NEPC). NMYC elicits its oncogenic effects by forming a heterodimer with MAX. This complex binds to regulating elements and activates the transcription of MYC target genes that play roles in tumor growth and progression. It is well known that members of the MYC family of proteins make compelling targets for cancer treatments. However, to this date, no tangible drug candidates have been developed into the clinics for MYC. In previous studies utilizing a rational computer-aided drug discovery (CADD) approach, we identified VPC-70551 as our most active hit. Subsequent optimization with the VPC-70551 scaffold has led to the identification of a new series of compounds. Using in silico drug screening followed by functional validation, we identified a small molecule inhibitor, VPC-70619, that exhibits higher microsomal stability and is better absorbed and tolerated orally than most MYC inhibitors described in the literature. Method: We used a transcriptional reporter assay to determine the effect of VPC-70619 on MYC-mediated transcription. To validate on-target effect, we evaluated the effect of VPC-70619 treatment on MYC-positive (LASCPC-01, NCIH660, LNCaP N-MYC, 22Rv1 N-MYC) and MYC-negative (HO15.19) cancer cells. We also evaluated the effect of VPC-70619 on MYC/MAX interaction by PLA and on DNA binding by BLI. The direct binding between recombinant MYC/MAX protein complex and VPC-70619 was evaluated by MST. Results: VPC-70619 inhibited MYC transcriptional activity in dose dependent manner and the proliferation of MYC-positive cell lines. VPC-70619 did not interfere with MYC/MAX interaction however it blocked the complex interaction with DNA. We confirmed the direct binding of VPC-70619 to the purified MYC/MAX complex by using MST. Conclusion: This project presents the identification of a new MYC inhibitor that blocks the transcriptional activity of this oncogene and elucidates the molecular mechanism of action of this inhibitor. Our findings help prelude the development and discovery of more effective treatments for NEPC patients. Citation Format: Jane Foo, Anh-Tien Ton, Kriti Singh, Fuqiang Ban, Helene Morin, Joseph Lee, Eric LeBlanc, Nada Lallous, Artem Cherkasov. Structure-based development of a novel MYC inhibitor for neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5731.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 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) | 0.001 | 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 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".