Lung cancer has the highest rate of morbidity and mortality among various cancer types, being responsible for over 1.69 million deaths per year. Approximately 80–85% of the lung cancer patients diagnosed present non-small cell lung cancer (NSCLC), while 10–15% present small cell lung cancer (SCLC). Mutations in the epidermal growth factor receptor (EGFR) have been observed in ∼50% of patients, in particular, in East Asian NSCLC patients. The single-point mutation L858R (exon 21) and amino acids deletions in the tyrosine kinase (TK) domain (exon 19) constitute 90% of all EGFR-activating mutations.
We introduced an acrylamide group as a Michael acceptor, resulting in compound 2, which showed potent in vitroactivity in both wild and mutant EGFR kinases and potent anti-proliferative activity in HCC827 lung cancer cell line. In this work, we apply SBDD to guide the optimization of lead compound 2and perform a detailed structure-activity relationship (SAR) study to bring this drug candidate into the next development stage.
We optimized the compound 2by scaffold hopping and by exploiting the potent inhibitory activity of various warhead groups. The results of the multi-objective optimization obtained the clinical candidate, compound 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFR L858R/T790M double mutations, but also exhibited 10-fold potency better than 3rd generation inhibitor, osimertinib, against three EGFR and one HER2 exon 20 insertion mutations, since there are currently no EGFR-directed therapies approved specifically for the treatment of this mutation.
X-ray co-crystal study of EGFRWTKinase and compound 78 revealed the potential of future design for mutant-selective inhibitors. Finally, furanopyrimidine 78 was selected as a clinical candidate to conduct all preclinical experiments and is currently undergoing phase 1 clinical trial in Taiwan.
Clinical trial identification
Legal entity responsible for the study
National Health Research Institutes, Taiwan.
All authors have declared no conflicts of interest.