Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors

Abstract

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 enzymatic 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 IC values of 91.7 nM and 1.2 μM, respectively. Notably, 27b dramatically reduced the viability of various patient-derived cancer cells preferentially overexpressing EGFR/HER2 (A431, MDA-MBA-361 and SKBr3 with IC values of 1.45, 3.5 and 4.83 μM, respectively). Additionally, 27b efficiently thwarted the proliferation of lapatinib-resistant human non-small lung carcinoma (NCI-H1975) cells, harboring T790 M mutation, with IC 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.

Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma

“…Moreover, 10a exhibited impressive preferential activity against HDAC6 when compared to the inhibiting activity of the same derivative against all the other isoforms that represent class I (HDAC1, HDAC2, HDAC3, HDAC8), class IIa (HDAC4, HDAC5, HDAC7, HDAC9), class IIb (HDAC10) and class IV (HDAC11) (Table 1). There was no need to measure the corresponding IC 50 values 71 of 10a against other HDAC isoforms due to the weak inhibiting activity that didn’t reach 75% against any isoform (Table 1). The % inhibition was enough to highlight 10a that showed significant preference against HDAC6.…”

Involvement of cancer-derived EMT cells in the accumulation of 18F-fluorodeoxyglucose in the hypoxic cancer microenvironment

“…Although this observation regarding grain distribution was consistent with the results of macro-autoradiography reported by Shangguan et al 24 , this is the first study to demonstrate high 18 F-FDG uptake using micro-autoradiography in combination with analysis of pimonidazole distribution. Our data shows that HER2 amplification was observed in regions showing a loss of EGFR expression; anti-EGFR therapy has been therefore used as a basis for targeting tumors expressing EGFR 41 – 44 . These results may explain the correlation between high SUV max in 18 FDG-PET and resistance to EGFR inhibitor or EGFR-TK inhibitor in clinical studies.…”

TMLRpred: A machine learning classification model to distinguish reversible EGFR double mutant inhibitors

“…Also, the ether linker helps in the orientation of the compound and anilino derivative of substituted aniline that can fit into the back pocket of EGFR. In addition, aniline ring interacts with the Lys745 that interrupts the formation of salt bridge with the Glu762 and hinders the active protein conformation (Milik et al., 2018).…”