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 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 of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using an In Silico Enabled Drug Discovery Platform.

Igawa H ，Konst ZA ，Therrien E ，Shelley M ，Koldsø H ，Bos PH ，Negri A ，Verras A ，Guo J ，Dahlgren MK ，Levinson A ，Parr BT ，Kurhade SE ，Latthe P ，Shetty R ，Santhanakrishnan S ，Amberg-Johnson K ，Futran AS ，Atsriku C ，Pelletier RD ，Liu Z ，Bell JA ，Bhat S ，Svensson M ，Gerasyuto AI ... -  《-》

From challenges to solutions: A review of fourth-generation EGFR tyrosine kinase inhibitors to overcome the C797S triple mutation in non-small cell lung cancer.

This Review discusses recent advancements in the development of fourth-generation "Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs)" targeting resistance mutations, with an emphasis on the C797S mutation in "Non-small Cell Lung Cancer (NSCLC)". While first, second, and third-generation EGFR-TKIs have made significant progress in overcoming EGFR kinase resistance, the emergence of the EGFR-C797S mutation poses a substantial challenge, particularly in the context of resistance to Osimertinib. Fourth-generation TKIs are classified into ATP-competitive, allosteric, and ortho-allosteric inhibitors, with the goal of enhancing specificity for mutant EGFR while minimizing off-target effects on wild-type EGFR to reduce toxicity. This Review provides a detailed analysis of structural modifications and their impact on drug potency and selectivity, with the aim of improving efficacy against resistant NSCLC. Preclinical and early-phase clinical trials of these inhibitors are promising, though further optimization of pharmacokinetic and safety profiles is crucial for future clinical success. This work offers key insights for medicinal chemists in the design and development of fourth-generation EGFR inhibitors to address drug-resistant mutations in NSCLC.

Ahmad I ，Patel HM 《-》