ABSTRACT
INTRODUCTION: EGFR has been implicated in various malignancies such as NSCLC, breast, head and neck, and pancreatic cancer. Numerous drugs have been developed in order to target the tyrosine domain of EGFR as an approach in cancer treatment. AREAS COVERED: This article focuses on the different generations of EGFR tyrosine kinase inhibitors (TKIs). This spans from the emergence of the first-generation EGFR-TKIs to overcoming drug resistance using second-generation EGFR-TKIs and to reducing adverse effect (AE) using mutant-selective third-generation EGFR-TKIs. EXPERT OPINION: Current TKI treatment is frequently accompanied by drug resistance and/or serious AEs. There has been the promise of advancements in second-generation EGFR-TKIs that could overcome drug resistance, acting as second- or third-line salvage treatment, but this promise has yet to be met. That being said, both issues are currently being addressed with mutant-selective EGFR-TKIs with the expectation of bringing more EGFR-targeted therapy into the next phase of cancer therapy in the future.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Drug Design , Drug Resistance, Neoplasm , ErbB Receptors/genetics , Humans , Molecular Targeted Therapy , Mutation , Neoplasms/genetics , Neoplasms/pathology , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacologyABSTRACT
Computer-guided drug design is a powerful tool for drug discovery. Herein we disclose the use of this approach for the discovery of dual FMS-like receptor tyrosine kinase-3 (FLT3)-Aurora A inhibitors against cancer. An Aurora hit compound was selected as a starting point, from which 288 virtual molecules were screened. Subsequently, some of these were synthesized and evaluated for their capacity to inhibit FLT3 and Aurora kinase A. To further enhance FLT3 inhibition, structure-activity relationship studies of the lead compound were conducted through a simplification strategy and bioisosteric replacement, followed by the use of computer-guided drug design to prioritize molecules bearing a variety of different terminal groups in terms of favorable binding energy. Selected compounds were then synthesized, and their bioactivity was evaluated. Of these, one novel inhibitor was found to exhibit excellent inhibition of FLT3 and Aurora kinase A and exert a dramatic antiproliferative effect on MOLM-13 and MV4-11 cells, with an IC50 value of 7 nM. Accordingly, it is considered a highly promising candidate for further development.
Subject(s)
Antineoplastic Agents/pharmacology , Aurora Kinase A/antagonists & inhibitors , Computer-Aided Design , Drug Design , Protein Kinase Inhibitors/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aurora Kinase A/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
The regioselective 1,3-dipolar cycloaddition of alpha-bromo-pentafluorophenyl vinylsulfonate with nitrile oxides has been used to rapidly access a range of 3,5-isoxazoles which could be converted directly to their corresponding sulfonamides.
