Discovery of Novel Allosteric Mitogen-Activated Protein Kinase Kinase (MEK) 1,2 Inhibitors Possessing Bidentate Ser212 Interactions

Using structure-based design, two novel series of highly potent biaryl amine mitogen-activated protein kinase kinase (MEK) inhibitors have been discovered. These series contain an H-bond acceptor, in a shifted position compared with previously disclosed compounds, and an adjacent H-bond donor, resulting in a bidentate interaction with the Ser212 residue of MEK1. The most potent compound identified, <b>1</b> (G-894), is orally active in in vivo pharmacodynamic and tumor xenograft models

Pyridones as Highly Selective, Noncovalent Inhibitors of T790M Double Mutants of EGFR

The rapid advancement of a series of noncovalent inhibitors of T790M mutants of EGFR is discussed. The optimization of pyridone <b>1</b>, a nonselective high-throughput screening hit, to potent molecules with high levels of selectivity over wtEGFR and the broader kinome is described herein

Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study

Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8–14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del­(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model