Discovery of Potent and Wild-Type-Sparing Fourth-Generation EGFR Inhibitors for Treatment of Osimertinib-Resistance NSCLC

Osimertinib resistance is an unmet clinical need for the treatment of non-small cell lung cancer (NSCLC), and the main mechanism is tertiary C797S mutation of epidermal growth factor receptor (EGFR). To date, there is no inhibitor approved for the treatment of Osimertinib-resistant NSCLC. Herein, we reported a series of Osimertinib derivatives as fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited the EGFRL858R/T790M/C797S mutant with an IC50 value of 14 nM and suppressed the proliferation of H1975-TM cells with an IC50 value of 14 nM, which show over 500-fold selectivity against wild-type forms. Moreover, D51 inhibited the EGFRdel19/T790M/C797S mutant and the proliferation of the PC9-TM cell line with IC50 values of 62 and 82 nM. D51 also exhibited favorable in vivo druggability, including PK parameters, safety properties, in vivo stability, and antitumor activity.

 

Comments：

The tertiary C797S mutation of EGFR is a well-known mechanism of resistance to Osimertinib, and the lack of approved inhibitors for the treatment of Osimertinib-resistant NSCLC presents an unmet clinical need.

It is promising to hear that the Osimertinib derivatives, particularly the top candidate D51, were rationally designed and potently inhibited the EGFRL858R/T790M/C797S mutant, which is a common mutation associated with resistance to Osimertinib. D51 also showed selectivity against wild-type forms and inhibited the EGFRdel19/T790M/C797S mutant, which is another mutation commonly associated with Osimertinib resistance.

The fact that D51 demonstrated favorable in vivo druggability, including PK parameters, safety properties, in vivo stability, and antitumor activity, is particularly encouraging. It suggests that D51 has the potential to become a promising therapeutic option for patients with Osimertinib-resistant NSCLC. However, further studies, including clinical trials, will be necessary to fully evaluate its safety and efficacy.

Related Products

Cat.No.	Product Name	Information
S7297	Osimertinib (AZD9291)	Osimertinib (AZD9291) is an oral, irreversible, and mutant-selective EGFR inhibitor with IC50 of 12.92, 11.44 and 493.8 nM for Exon 19 deletion EGFR, L858R/T790M EGFR, and WT EGFR in LoVo cells, respectively. Phase 3.

Related Targets

EGFR