Background: Lung cancer is the major cause of cancer death in the world while non small cell lung cancer (NSCLC) accounts approximately 85% of all lung cancer diagnosis. EGFR mutations, found in 10–30% of patients with NSCLC characterize a subpopulation with exquisite sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, the clinical benefits of first-generation TKIs (like gefitinib or erlotinib) can be further improved because of the development of drug-acquired resistance within 10–14 months in patients who initially respond to the treatment. Therefore, there is a need to discover next generation medicines as EGFR-TKIs for NSCLC patients. Methods: Our EGFR program was first started to screen 20,000 in-house compounds for EGFR (wild type, 32D- EGFRWild-Type) activity in EGFR-transfected 32D cells and further performed knowledge-based design. More than 300 analogues were synthesized in this series and US and ROC patents were granted in 2013 and PCT patent application is under examination. We had identified DBPR112 as a potent EGFR-TKI with oral in vivo activity in a mouse model for lung adenocarcinoma. Results: DBPR112 showed IC50 of 2 nM in HCC827 cells and potent EGFRWild-Type (IC50: 10 nM) and EGFRL858R/T790M (IC50: 70 nM) kinase inhibition which are better than gefitinib and similar to that of BIBW2992 (Afatinib, developed by Boehringer Ingelheim) that is currently under phase III clinical trial. DBPR112 was orally (F = 49%) administered against the growth of human lung HCC827 tumors subcutaneously xenografted in nude mice. A dramatic reduction of the tumor size was noted in the tumors treated with DBPR112 without significant loss of body weights in the nude mice. In addition, the pharmacokinetics properties of DBPR112 are superior to those of Afatinib. Conclusion: Considering the fact that EGFR kinase plays an important role in lung adenocarcinoma with drug-sensitive mutations in EGFR, our goal is to develop novel and potent EGFR kinase inhibitors for the treatment of lung cancer, either as a single agent or in combination with existing cancer treatment. DBPR112 is a highly potent small-molecule against various forms of EGFR kinase. The non-clinical profile of DBPR112 showed promising in vivo efficacy. We, therefore, propose to design a preclinical program to assess the developability of DBPR112 and conduct comprehensive preclinical studies. We hope to make DBPR112 an investigational new drug for the treatment of lung cancer in the near future.
Date:
2013-11
Relation:
Journal of Thoracic Oncology. 2013 Nov;8(Suppl. 2):S779-S780.
