A Potent and Reversible EGFR Inhibitor (E)-AG 99

By Louis Gilman April 22, 2019 #EGFR

(E)-AG 99 is a potent and reversible EGFR inhibitor and has potential treatment Bladder cancer. Bladder cancer (BC) is one of common malignancies worldwide.

Bladder cancer is any of several types of cancers arising from the tissues of the urinary bladder. The prevalence of EGFR expression in bladder cancer cell lines makes it a viable therapy in at least basal-like tumors. The basal phenotype is enriched for EGFR activation/amplification, can be found in almost 25% of bladder tumors. A potential therapeutic target is the epidermal growth factor receptor (EGFR). EGFR over-expresses in up to 74% of bladder cancer tissue specimens. However, EGFR has a relatively low expression in normal urothelium. In addition, EGFR is an independent predictor of decreased survival and stage progression in Bladder cancer.

In this study, Natsumi Yamamoto, et al use the human bladder carcinoma cell line 5637 as a model system. The human bladder carcinoma cell line 5637 can undergo adaptation to serum-free conditions by autocrine growth stimulation. This autocrine growth involves EGFR and its ligands including EGF, TGF-α, amphiregulin and heparin-binding EGF (HB-EGF). This amplification and luminal localization of EGFR in urothelial tumors make intravesical therapy a potential treatment option in bladder cancer.

(E)-AG 99 is a potent inhibitor of EGFR. It is found inside the ATP pocket, consistent with its mode of inhibition competitive with respect to ATP. (E)-AG 99 effectively blocks tyrosine phosphorylation of c-Met at p145 site. AG99 also promotes cell death accompanied by activation of caspase-like proteases. (E)-AG 99 shows an inhibitory effect on both normal as well as serum-starved culture conditions. Moreover, (E)-AG 99 has a growth-inhibitory targets other than EGFR. On the other hand, the EGFR inhibitor (E)-AG 99 shows a growth-inhibitory effect on not only serum-starved cells but also normally grown cells. In summary, (E)-AG 99 is a potent EGFR inhibitor with potent in vitro and in vivo activity, demonstrates in bladder cancer models.