The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity
نویسندگان
چکیده
Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.
منابع مشابه
Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade
RET (REarranged during Transfection) is a receptor tyrosine kinase, which plays pivotal roles in regulating cell survival, differentiation, proliferation, migration and chemotaxis. Activation of RET is a mechanism of oncogenesis in medullary thyroid carcinomas where both germline and sporadic activating somatic mutations are prevalent. At present, there are no known specific RET inhibitors in c...
متن کاملApplication of 3D-QSAR on a Series of Potent P38-MAP Kinase Inhibitors
One of the most applied methods in drug industry for development of new drugs is 3D-QSAR methodology. As p38-mitogen-activated protein kinase (p38-MAPK) plays a crucial role in regulating the production of such proinflammatory cytokines as tumor necrosis factor-α (TNF-α) and interleukin-1, emerging as an attractive target for new anti-inflammatory agents, we used a 3D-QSAR based method of Compa...
متن کاملRho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension
In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells dec...
متن کاملDiscovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2)
We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as we...
متن کاملSynthesis, X-Rays Analysis, Docking Study and Cholinesterase Inhibition Activity of 2,3-dihydroquinazolin-4(1H)-one Derivatives
In search of potent cholinesterase inhibitors, we have carried out the synthesis and biologically evaluation of various benzaldehyde based 2,3-dihydroquinazolin-4(1H)-one derivatives. In vitro assay results revealed that all the synthesized compounds showed activity against both enzymes (AChE and BChE) and in few cases, the inhibition activity was even higher than or comp...
متن کامل