Milik, Sandra N. published the artcileSurmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors, Category: chlorides-buliding-blocks, the publication is European Journal of Medicinal Chemistry (2018), 316-336, database is CAplus and MEDLINE.
In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymic affinities. Guided by the binding mode of the marketed dual EGFR/HER2 inhibitor, Lapatinib, we proposed the design of dual EGFR/HER2 inhibitors based on the 6-phenylthieno[2,3-d]pyrimidine as a core scaffold and hinge binder. After two cycles of screening aiming to identify the optimum aniline headgroup and solubilizing group, we eventually identified 27b as a dual EGFR/HER2 inhibitor with IC50 values of 91.7 nM and 1.2 μM, resp. Notably, 27b dramatically reduced the viability of various patient-derived cancer cells preferentially overexpressing EGFR/HER2 (A431, MDA-MBA-361 and SKBr3 with IC50 values of 1.45, 3.5 and 4.83 μM, resp.). Addnl., 27b efficiently thwarted the proliferation of lapatinib-resistant human non-small lung carcinoma (NCI-H1975) cells, harboring T790 M mutation, with IC50 of 4.2 μM. Consistently, 27b significantly blocked EGF-induced EGFR activation and inactivated its downstream AKT/mTOR/S6 signalling pathway triggering apoptotic cell death in NCI-H1975 cells. The present study presents a promising candidate for further design and development of novel EGFR/HER2 inhibitors capable of overcoming EGFR TKIs resistance.
European Journal of Medicinal Chemistry published new progress about 350-30-1. 350-30-1 belongs to chlorides-buliding-blocks, auxiliary class Fluoride,Chloride,Nitro Compound,Benzene, name is 3-Chloro-4-fluoronitrobenzene, and the molecular formula is C6H3ClFNO2, Category: chlorides-buliding-blocks.
Referemce:
https://en.wikipedia.org/wiki/Chloride,
Chlorides – an overview | ScienceDirect Topics