Proteolysis-targeting chimeras (PROTACs) are a promising new class of drugs that selectively degrade cellular proteins of interest. PROTACs that target oncogene products are avidly being explored for cancer therapies, and several are currently in clinical trials. Drug resistance is a substantial challenge in clinical oncology, and resistance to PROTACs has been reported in several cancer cell models. Here, using proteomic analysis, we found intrinsic and acquired resistance mechanisms to PROTACs in cancer cell lines mediated by greater abundance or production of the drug efflux pump MDR1. PROTAC-resistant cells were resensitized to PROTACs by genetic ablation of
ABCB1
(which encodes MDR1) or by coadministration of MDR1 inhibitors. In MDR1-overexpressing colorectal cancer cells, degraders targeting either the kinases MEK1/2 or the oncogenic mutant GTPase KRAS
G12C
synergized with the dual epidermal growth factor receptor (EGFR/ErbB)/MDR1 inhibitor lapatinib. Moreover, compared with single-agent therapies, combining MEK1/2 degraders with lapatinib improved growth inhibition of MDR1-overexpressing KRAS-mutant colorectal cancer xenografts in mice. Together, our findings suggest that concurrent blockade of MDR1 will likely be required with PROTACs to achieve durable protein degradation and therapeutic response in cancer.
The interaction and corrosion inhibition properties of methyl carbamate on copper metal in 1 N HNO 3 have been studied by polarization, electrochemical impedance spectroscopy (EIS), adsorption, surface studies and computational calculations at 300 K. Polarization studies showed that methyl carbamate act as a cathodic type inhibitor. The inhibitive action of this molecule is discussed in terms of blocking the electrode surface by the adsorption of inhibitor molecules obeying Langmuir isotherm. In addition, the local reactivity, analyzed through Fukui functions, shows that the sulphur atom will be the most probable adsorption site. A quantum chemical approach is used to calculate electronic properties of the molecule to ascertain the relation between inhibitive effect and molecular structure.
Amino acids and its Schiff bases have been widely recognized as green corrosion inhibitors primarily due to its non-toxic nature and biodegradable properties. Considering its unique nature and significant contribution in corrosion chemistry, studies were undertaken with an objective to find out the inhibitory effect of L-serine based Schiff base HHDMP on copper in 0.5, 1.0 and 1.5 M of sulphuric acid at 303, 308 and 313 K. Various techniques such as weight loss method, electrochemical impedance spectroscopy, potentiodynamic polarization (Tafel), basic computational calculations and adsorption studies were employed in the present investigations. Results revealed that Schiff base HHDMP do offer attractive inhibition efficiency in all concentrations of sulphuric acid. The inhibition effect advanced with the increased concentration of the inhibitor. However, with the increased concentration, the inhibition efficiency showed decline trend. Such behaviour of the amino acid Schiff base HHDMP on copper in sulphuric acid may be due to surface adsorption of the inhibitor molecules on the metal, which contributes to decrease in the double-layer capacitance and increase in the polarization resistance.
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