Direct Ser797 Interacted Pteridine-7(8H)-one Derivatives as Highly Selective and Orally Available...

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Acquired resistance to Osimertinib in non-small cell lung cancer (NSCLC) is frequently driven by the EGFR C797S mutation.
• There is a critical need for novel small-molecule inhibitors to overcome this Osimertinib resistance.

Purpose of the Study:

• To develop novel pteridin-7(8H)-one-derived inhibitors targeting EGFR mutations, specifically EGFR L858R/T790M/C797S (EGFR LR/TM/CS).
• To identify inhibitors that interact with the mutated Ser797 residue and the surrounding hydrophobic pocket.

Main Methods:

• Design and synthesis of pteridin-7(8H)-one derivatives.
• In vitro enzymatic assays to determine inhibitory activity (IC50) and kinase selectivity.
• Pharmacokinetic studies in vivo.
• Antitumor efficacy evaluation in a BaF3-EGFR LR/TM/CS xenograft model.

Main Results:

• Compound M49 demonstrated potent inhibition of EGFR LR/TM/CS with an IC50 of 18.94 nM and high kinase selectivity (S35 = 0.005).
• Oral administration of M49 showed favorable pharmacokinetic properties, including a Cmax of 230.07 ng/mL and 12.14% oral bioavailability.
• M49 exhibited superior antitumor efficacy compared to Brigatinib in the BaF3-EGFR LR/TM/CS xenograft model, achieving a tumor growth inhibition (TGI) of 73.53% versus 56.05%.

Conclusions:

• A novel strategy for discovering EGFR LR/TM/CS inhibitors was established.
• Pteridin-7(8H)-one-based compound M49 represents a promising candidate for overcoming Osimertinib resistance in NSCLC due to its potent in vitro and in vivo activity and selectivity.