Abstract 5479: Discovery and evaluation of GT19630, a c-Myc/GSPT1 cereblon E3 ligase modulator (CELMoD), for targeting Myc-driven blood cancers and small cell lung cancers (SCLC)
Bibliographic record
Abstract
Abstract c-Myc is an oncogenic transcriptional factor driving tumor initiation, progression and poor prognosis in 80% of all tumor types, especially in B-cell malignancies and small cell lung cancer (SCLC) with Myc genomic alterations. Myc dysregulation have been directly linked to the poor clinical outcome in these cancers. Therefore, it is highly warranted to discover and develop novel Myc therapeutical agents for targeting Myc driven cancers. Here we described GT19630, a GSPT1/Myc CELMoD. GT19630 was discovered through an SAR effort for c-Myc degrader by using c-Myc ELISA and Western blot assays in c-Myc driven HL60 AML cells. GT19630 selectively degraded c-Myc proteins in HL60 cells (IC50=1.5 nM) as compared to growth-factor regulated c-Myc erythroid progenitor cells (TF-1 cells) with IC50=52.5 nM. GT19630 also selectively inhibited HL60 cell proliferation (IC50= 0.33 nM), as compared to its IC50 (26.2 nM) in GM-CSF-TF-1 proliferation, as well as in bone marrow colony-forming cell assays (myeloid=40.2 nM), suggesting>100X selectivity for HL60 cells over normal blood cells. Through the SAR for Myc degrader, GT19630 has been evolved as a leading molecule sharing chemical properties to CELMoDs. Therefore, this compound was further evaluated by proteomics and western blot, GT19630 was confirmed to selective degradation of CELMoD targets, GSPT1/GSPT2 (translation termination factor G1 to S phase transition proteins 1 and 2) with IC90<1 nM and CK1 alpha (IC90<10 nM), but not IKZF1/Ikaros. In silico modeling of GT19630 was performed in the DDB1−CRBN−CC-885−GSPT1 complex and confirmed the docking similarity with CELMoDs. Further, GT19630 inhibited the cell proliferation with IC50<10 nM in 74% B-cell malignant cell lines (20/27) bearing deregulated c-Myc and in 79% of SCLC cell lines (4/19) carrying deregulated Myc (c-Myc, N-Myc or L-Myc) tested. Moreover, GT19630 completely degraded Myc proteins in AML, lymphoma and multiple myeloma (c-Myc) and SCLC (c-Myc and N-Myc) xenograft tumors at the lowest dose of 1.0 mg/kg and induced complete tumor regression (lowest dose=0.3 mg/kg) tested. Furthermore, this compound eradicated lymphoma cells in Daudi-induced liquid lymphoma mouse models. In addition, GT19630, as a potent GSPT1/Myc CELMoD, demonstrated an even-driven pharmacology in vivo and induced complete tumor regression with a dosing regimen of 3 day on/7 day off. Remarkably, GT19630 selectively degraded Myc proteins in HL60 and DMS114 SCLC xenograft tumors as compared to a much less potency at degrading c-Myc in rat spleen. Finally, GT19630 demonstrated favorable PK and safety profiles (an 8-fold safety therapeutic windows) with no effect on myeloid lineages in rats at the dose of 6 mg/kg for 14 days, indicating GT19630 lacks myelosuppression as reported for other CELMoDs. Currently, GT19630 has been advanced into IND enabling stage. Citation Format: Liandong Ma, Youzhi Tong, Zhaohui Yang, Qianxiang Zhou, Hongha Yan, Ru Xu, Jie Chen, Jie Pan, Huiyuan Wang, Jiangwei Li, Dong Chen, Xiang Cai, Jie Qu, Yini Wang, Jun Qin, Yuki Nishida, Michael Andreeff, Qilnli Guo, Yuki Nishida, Michael Andreeff. Discovery and evaluation of GT19630, a c-Myc/GSPT1 cereblon E3 ligase modulator (CELMoD), for targeting Myc-driven blood cancers and small cell lung cancers (SCLC) [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 5479.
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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 | 0.000 |
| 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) | 0.000 | 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".