Lung cancer is one of the chief causes of cancer death in the world; in addition, non-small cell lung cancer (NSCLC) accounts for 85% of the lung cancer deaths. The development of tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have shown remarkable effects in patients but some acquired resistance after treatment. Therefore, the discovery of efficacious EGFR-TKIs poses an utmost priority. Our team at IBPR has designed and synthesized a series of compounds by high throughput parallel synthesis platform. In the subsequent structure-activity relationship study (SAR) and lead optimization, approximate 150 compounds were synthesized, which concluded that the presence of an N,N-dimethyl functional group on the Michael acceptor and the S-chirality of the phenylaminoethanol side chain were both essential. Consequently, DBPR112 was identified as a potent EGFR-TKI clinical candidate showing excellent inhibitory ability on EGFRL858R/T790M and EGFR exon 20 insertion. DBPR112 was orally effective against the growth of human lung H1975 tumors subcutaneously xenografted in nude mice. A dramatic reduction in tumor size was noted with DBPR112 treatment, while displaying negligible body weight loss in all dosing groups. Furthermore, DBPR112 was more tolerable than afatinib in mice. To date, all pre-clinical studies were completed, and the IND application of DBPR112 was approved by US FDA in 2016 and the Phase I clinical trial has been initiated since July 2017 in Taiwan.
Date:
2018-07
Relation:
Cancer Research. 2018 Jul;78(13, Suppl.):Meeting Abstract 4789.
