Abstract 3854: Preclinical characterization of a novel non-cyclic dinucleotide small molecule STING agonist with potent antitumor activity in mice
Bibliographic record
Abstract
The cGAS-STING pathway plays a pivotal role in sensing aberrant cytoplasmic DNA fragments derived from pathogens or host tumor cells and initiating an innate immune response. STING activation induces type I IFNs and a cascade of other pro-inflammatory cytokines that activate the innate immune system and subsequently recruit adaptive immune cells. STING functions as a key mediator bridging the innate and adaptive immune responses by stimulating anti-tumor antigen presentation and promoting effective T cell priming, thereby making STING activation an attractive target for cancer immunotherapy. Currently, all known STING agonists in clinical trials are based on a cyclic dinucleotide (CDN) scaffold. These molecules mimic the endogenous STING ligand cGAMP which displays limited potency and cell permeability. Here we present the preclinical characterization of a novel non-CDN small molecule STING agonist, TTI-10001.TTI-10001 exhibited potent and broad activity in a panel of HEK293T-STING reporter cell lines expressing each of the five human STING (hSTING) alleles or murine STING (mSTING). Activation of the STING pathway was confirmed by an increase of both phospho-STING and phospho-IRF3 after TTI-10001 treatment, and TTI-10001-dependent induction of reporter activity was ablated in the presence of an inhibitor of the downstream STING signaling kinase TBK1. TTI-10001 showed a favorable safety profile with no activity on hERG or major CYP450 isoforms and was well tolerated in mice with no weight loss or overt morbidity after repeat intratumoral administration. Mice dosed with TTI-10001 displayed increased levels of phospho-STING and phospho-IRF3 in tumors as well as elevated expression of various pro-inflammatory cytokines including IFNβ, TNFα, and IL-6. This in vivo activation of STING signaling correlated with significant anti-tumor activity in multiple syngeneic mouse tumor models.In summary, we have generated a novel non-CDN small molecule STING agonist with potent activity on the five hSTING alleles and mSTING. Our compound exhibits strong in vitro and in vivo induction of the STING pathway as well as potent anti-tumor activity. Taken together, these results highlight the potential of TTI-10001 and support further evaluation and development of this molecule as a novel cancer immunotherapy agent.Citation Format: Zezhou Wang, Peter Dove, David Rosa, Bolette Bossen, Simone Helke, Marilyse Charbonneau, Laura Brinen, Karen Dodge, Gloria H. Lin, Carole Galligan, Natasja N. Viller, Mark Wong, Vivian Lee, Tina Catalano, Robert A. Uger, Malik Slassi, Jeff Winston. Preclinical characterization of a novel non-cyclic dinucleotide small molecule STING agonist with potent antitumor activity in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3854.
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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) | 0.000 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".