ABSTRACT
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
Subject(s)
Acrylamides/pharmacology , Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/genetics , Chemistry Techniques, Synthetic , Drug Resistance, Neoplasm/drug effects , ErbB Receptors/genetics , Female , Humans , Inhibitory Concentration 50 , Lung Neoplasms/genetics , Male , Mice , Middle Aged , Mutation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Rats, Inbred Strains , Xenograft Model Antitumor AssaysABSTRACT
A new synthetic route to 3-(heteroaryl) tetrahydropyrazolo[3,4-c]pyridines has been developed that uses the Suzuki-Miyaura cross-coupling of a triflate 6 with (hetero)aryl boronic acids or esters. Using Pd(OAc)2 and XPhos or an XPhos precatalyst, a diverse range of substituents at the C3 position of the tetrahydropyrazolo[3,4-c]pyridine skeleton were prepared. The use of pivaloyloxymethyl and benzyl protection also offers the potential to differentially functionalize the pyrazole and tetrahydropyridine nitrogens.
Subject(s)
Benzyl Compounds/chemistry , Palladium/chemistry , Pyrazoles/chemistry , Pyrazoles/chemical synthesis , Pyridines/chemistry , Pyridines/chemical synthesis , Catalysis , Esters , Molecular StructureABSTRACT
Silenes, generated through thermolysis of acylpolysilanes, add to alpha,beta-unsaturated esters to form cyclobutanes and silylsubstituted cyclopropanes in moderate yields. Upon Si-C bond oxidation the cyclopropanes are converted directly to 1,4-dicarbonyl compounds, thus demonstrating the formal acyl anion chemistry of acyl polysilanes.