GIBH’s New Progress of Treating Non-small-cell Lung Cancer (NSCLC)

Small molecular EGFR inhibitors, gefinitib and erlotinib, were approved by US Food and Drug Administration in 2002 and 2004, respectively, and have achieved significant clinical benefit for non small cell lung cancer (NSCLC) patients. But their efficacy is eventually diminished because of acquired point mutations in the kinase domain of EGFR. Particularly, a single T790 M point mutation (threonine790→methionine790) at the “gatekeeper” position in EGFR accounts for approximately 50% in clinically acquired resistant patients. In order to overcome the T790M mutation related resistance, a number of irreversible ATP-competitive EGFR inhibitors have been developed. So far, there is still no small molecule drug toward EGFRT790M entering the market.

Prof. Ke Ding’s group at GIBH designed and synthesized a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl derivatives as novel EGFR inhibitors based on analyzing the X-ray complexes between the kinase EGFRT790M and small molecule inhibitors and using rational drug design strategy. The novel EGFR inhibitors exhibited remarkable potencies, with IC50 values in the high picomolar range against all types of EGFR kinase, including the clinical resistance-related EGFRT790M mutant. The compounds also potently inhibited the proliferation of NSCLC cells bearing EGFRdel E746‑A750 or EGFRL858R/T790M mutants. One of the most potent inhibitors, CSH-EGF29, displayed significant in vivo anticancer efficacy in a H1975 human NSCLC cancer xenograft mouse model, representing a new, promising lead compound with a different chemical scaffold for further development of EGFR inhibitors to overcome EGFRT790M mutation-induced clinical resistance to gefitinib and erotinib. The research was published in Journal of Medicinal Chemistry in February 2012 (DOI: 10.1021/jm201591k).

The research was supported by National Basic Research Program of China, National Natural Science Foundation, Key Project on Innovative Drug of Guangdong Province, Strategic Collaborative Project of Guangdong Province and Chinese Academy of Sciences, Key Project on Innovative Drug of Guangzhou City, and the 100-talent program of Chinese Academy of Sciences (CAS).

Contributor：Shaohua Chang Chemical Biology Institute