Abstract 1352: Mechanism of action of AL622, a molecule rationally designed to release an EGFR and a Src kinase inhibitor
Bibliographic record
Abstract
Abstract In many solid tumors, including prostate and breast carcinomas, it has now been shown that Src synergizes with EGFR to promote cell proliferation and invasion. While molecules with EGFR and Src targeting functions have been designed, prodrugs capable of releasing optimized inhibitors of the two targets are scant. We designed AL622, which contains a quinazoline head targeted to EGFR and a hydrolysable linker that connects it to the PP2-like structure. HPLC analysis showed that this molecule is capable of releasing an EGFR inhibitor and intact PP2 inside the cells. The growth inhibition of AL622 in a panel of isogenic NIH3T3 cell lines (wt, Neu/ErbB2 and Her14/EGFR transfected) in comparison with Gefitinib (a clinically approved strong EGFR inhibitor) and PP2 (a Src-inhibitor) was assessed using the SRB assay. Like Gefitinib, AL622 blocked the proliferation of NIH3T3 cells transfected with the EGFR or Her2 gene. Although Gefitinib was twice as potent, AL622 showed a higher selectivity (fold selectivity = 1.77 for Neu-transfected and 1.63 for HER14-transfected cells). On the other hand, AL622 showed a 5-fold greater potency than PP2 in the EGFR and Her2 transfected cells. It was also much more selective than PP2 (fold selectivity = 35.9 for Neu-transfected and 37.8 for HER14-transfected cells). Western blot analysis in MDA-MB231 cells known to be characterized by Src-EGFR interaction showed that AL622 was capable of inducing a dose-dependent inhibition of EGFR and Src. In contrast, PP2 at an equidose was incapable of blocking EGFR but induced potent Src-inhibition. While Gefitinib induced some Src inhibition, it was less potent than AL622. Results from the wound healing assay showed that AL622 was capable of blocking the motility of 4T1 mouse breast cancer cells at doses comparable with those of PP2. However, a Boyden Chamber invasion assay showed that AL622 was capable of inducing more significant inhibition of invasion when compared with PP2 or the combination of PP2 and Gefitinib. The results in toto suggest that designing molecules to inhibit Src and EGFR can be an effective strategy to block aggressive proliferation and invasion in tumor cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1352. doi:10.1158/1538-7445.AM2011-1352
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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) | 0.002 | 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".