Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors.

Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency (~60 pM) against the drug-resistant EGFR L858R/T790M and L858R/T790M/C797S, which was superadditive as compared with the parent molecules. The enhanced potency is attributed to factors stemming from the linker connection to the allosteric-site group and informs strategies to engineer linkers in bivalent agent design.

Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448).

Lazertinib (YH25448) is a novel third-generation tyrosine kinase inhibitor (TKI) developed as a treatment for EGFR mutant non-small cell lung cancer. To better understand the nature of lazertinib inhibition, we determined crystal structures of lazertinib in complex with both WT and mutant EGFR and compared its binding mode to that of structurally related EGFR TKIs. We observe that lazertinib binds EGFR with a distinctive pyrazole moiety enabling hydrogen bonds and van der Waals interactions facilitated through hydrophilic amine and hydrophobic phenyl groups, respectively. Biochemical assays and cell studies confirm that lazertinib effectively targets EGFR(L858R/T790M) and to a lesser extent HER2. The molecular basis for lazertinib inhibition of EGFR reported here highlights previously unexplored binding interactions leading to improved medicinal chemistry properties compared to clinically approved osimertinib (AZD9291) and offers novel strategies for structure-guided design of tyrosine kinase inhibitors.

Magnetic Properties of CoFe2O4 Thin Films Synthesized by Radical-Enhanced Atomic Layer Deposition.

A radical-enhanced atomic layer deposition (RE-ALD) process was developed for growing ferrimagnetic CoFe2O4 thin films. By utilizing bis(2,2,6,6-tetramethyl-3,5-heptanedionato) cobalt(II), tris(2,2,6,6-tetramethyl-3,5-heptanedionato) iron(III), and atomic oxygen as the metal and oxidation sources, respectively, amorphous and stoichiometric CoFe2O4 films were deposited onto SrTiO3 (001) substrates at 200 °C. The RE-ALD growth rate obtained for CoFe2O4 is ∼2.4 Å/supercycle, significantly higher than the values reported for thermally activated ALD processes. Microstructural characterization by X-ray diffraction and transmission electron microscopy indicate that the CoFe2O4 films annealed between 450 and 750 °C were textured polycrystalline with an epitaxial interfacial layer, which allows strain-mediated tuning of the magnetic properties given its highly magnetostrictive nature. The magnetic behavior was studied as a function of film thickness and annealing temperature: saturation magnetization (Ms) ranged from 260 to 550 emu/cm3 and magnetic coercivity (Hc) ranged from 0.2 to 2.2 kOe. Enhanced magnetic anisotropy was achieved in the thinner samples, whereas the overall magnetic strength improved after annealing at higher temperatures. The RE-ALD CoFe2O4 thin films exhibit magnetic properties that are comparable to both bulk crystal and films grown by other deposition methods, with thickness as low as ∼7 nm, demonstrating the potential of RE-ALD for the synthesis of high-quality magnetic oxides with large-scale processing compatibility.