Design, synthesis, and antitumor activity evaluation of potent fourth-generation EGFR inhibitors for treatment of Osimertinib resistant non-small cell lung cancer (NSCLC).

Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent. In this study, we clarified the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against human triple (Del19/T790M/C797S) mutation. Representative compound 52 showed potent inhibitory activity against EGFRL858R/T790M/C797S with an IC50 of 0.55 nM and significantly inhibited the proliferation of the Ba/F3 cell line harboring EGFRL858R/T790M/C797S with an IC50 of 43.28 nM. Moreover, 52 demonstrated good pharmacokinetic properties and excellent in vivo efficacy. Overall, the compound 52 can be considered a promising candidate for overcoming EGFR C797S-mediated mutations.

Zhang Y ，Tong L ，Yan F ，Huang P ，Zhu CL ，Pan C ... -  《-》

Design, Synthesis, and Biological Evaluation of Novel Diaminopyrimidine Macrocycles as Fourth Generation Reversible EGFR Inhibitors That Overcome Clinical Resistance to Osimertinib Mediated by C797S Mutation.

Hu S ，Tong L ，Qin Q ，Wen J ，Li Y ，Feng F ，Wu K ，Zhou Y ，Shang J ，Wang J ，Liu J ，Xie H ，Lu X ... -  《-》

Discovery and preclinical evaluations of drug candidate DA-0157 capable of overcoming EGFR drug-resistant mutation C797S and EGFR/ALK co-mutations.

Activating mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are significant oncogenic drivers in non-small cell lung cancer (NSCLC) patients. Despite several approved EGFR and ALK inhibitors, drug-resistant mutations pose a major challenge. Especially, there is currently no approved EGFR inhibitors targeting the C797S mutation, a refractory mutation resistant to the third-generation EGFR inhibitors. Furthermore, an increasing number of patients with EGFR/ALK co-mutations have been identified in clinical practice, yet there are no effective therapeutic options available for them. In this study, we report the discovery and preclinical evaluations of a new small-molecule drug candidate, DA-0157, which is capable of overcoming EGFR drug-resistant mutation C797S and EGFR/ALK co-mutations. DA-0157 demonstrated excellent in vitro efficacy, significantly inhibiting various EGFRC797S mutants resistant to the third-generation EGFR inhibitors, ALK rearrangements, and EGFR/ALK co-mutations. In vivo studies revealed that DA-0157 substantially inhibited tumor growth in the LD1-0025-200717 EGFRDel19/T790M/C797S PDX model (40 mg/kg/d, TGI: 98.3 %), Ba/F3-EML-4-ALK-L1196 M CDX model (40 mg/kg/d, TGI: 125.2 %), and NCI-H1975 EGFRDel19/T790M/C797S & NCI-H3122 (EML4-ALK) dual-side implantation CDX model (40 mg/kg/d, TGI: 89.5 % & 113.9 %). DA-0157 demonstrates favorable pharmacokinetic properties and safety. Currently, DA-0157 (DAJH-1050766) is undergoing Phase I/II clinical trials.

He P ，Li H ，Yang Z ，Zhang R ，Ye Q ，Deng T ，Li W ，He S ，Dong G ，Yu Z ，Li Y ... -  《-》

[Non-small Cell Lung Cancer Cell Line PC-9 Drug-resistant Mutant Cell Line 
Establishment and Validation of Their Sensitivity to EGFR Inhibitors].

Hu T ，Lou Y ，Su M 《-》

Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting C797S Mutation.

Zhu Y ，Ye X ，Wu Y ，Shen H ，Cai Z ，Xia F ，Min W ，Hou Y ，Wang L ，Wang X ，Xiao Y ，Yang P ... -  《-》