Epidermal growth factor receptor (EGFR), a transmembrane protein, is a receptor of EGF family members of extracellular protein ligands. Specifically, EGFR expresses at elevated levels in different forms of cancer and is usually positively relevant to cancer progression and adverse prognosis. Different mutant forms of this protein also contribute to cancer heterogeneity. Besides, insufficient signaling of EGFR and other receptor tyrosine kinases in humans is associated with diseases such as Alzheimer’s disease. Moreover, EGFR dimerization stimulates its intrinsic intracellular protein tyrosine kinase activity. The kinase domain of EGFR can also cross phosphorylate the tyrosine residues of other receptors aggregated with it and can activate itself in this way.
Furthermore, blocking the EGFR binding site on the extracellular domain of the receptor or inhibiting the activity of intracellular tyrosine kinase interrupts EGFR signal transduction. We can prevent the growth of EGFR expressing tumors. Meanwhile, genotyping-based targeted therapy has become the standard treatment for NSCLC patients with carcinogenic EGFR mutations. Here, we will introduce an orally active EGFR inhibitor, DBPR112.
DBPR112 is an Orally Active EGFR (both WT and Mutant) Inhibitor.
First of all, DBPR112 is an orally active furanopyrimidine-based EGFR inhibitor. DBPR112 has IC50s of 15 nM and 48 nM for EGFRWT and EGFRL858R/T790M, respectively. Nonetheless, DBPR112 can occupy the ATP-binding site. DBPR112 has significant antitumor efficacy.
In the second place, DBPR112 with 0.32-1000 nM for 16 hours induces reduction of phosphorylated EGFR in a dose-dependent manner. Particularly, DBPR112 inhibits HCC827 (CC50=25 nM), H1975 (CC50=620 nM) and A431 Cell (CC50=1.02 μM) cell lines. Obviously, DBPR112 interacts with surrounding residues by covalent bonding, hydrogen bonds, and hydrophobic interactions. And this gives it a potent inhibitory activity against WT EGFR.
Last but not the least, DBPR112 with 20-50 mg/kg by orally for 5 days/week significantly reduces tumor growth in the HCC827 tumor model in 2 consecutive weeks. In particular, DBPR112 has a significant antitumor effect (mean tumor growth inhibition of 34%) in the H1975 tumor model. Additionally, DBPR112 with 5 mg/kg by IV has a T1/2 of 2.3 hours, a CL of 55.6 mL/min•kg, and a Vss of 8.6 L/kg for rats.
All in all, DBPR112 is an orally active EGFR (both WT and Mutant) inhibitor.