bibw-2992 and osimertinib

bibw-2992 has been researched along with osimertinib* in 2 studies

Other Studies

2 other study(ies) available for bibw-2992 and osimertinib

Article	Year
Discovery and optimization of covalent EGFR T790M/L858R mutant inhibitors. Bioorganic & medicinal chemistry letters, 2021, 11-15, Volume: 52 Epidermal growth factor receptor (EGFR) inhibitors have clinical utility in the treatment of non-small cell lung cancer (NSCLC) patients. Despite encouraging clinical efficacy with these agents, many patients develop resistance due to sensitizing (or activating) mutations ultimately leading to disease progression. In the majority of the cases, this resistance is due to the T790M mutation and frequently coexisting L858R. In addition, EGFR wild type receptor inhibition can lead to on target related dose limiting toxicities such as rash and diarrhea. We describe herein the identification of a mutant selective lead compound 12, an irreversible covalent inhibitor of EGFR T790M/L858R resistance mutations with selectivity over the wild type form. Significant tumor growth inhibition in preclinical models was observed with this lead. Topics: Acrylamides; Afatinib; Aniline Compounds; Dose-Response Relationship, Drug; Drug Discovery; ErbB Receptors; Humans; Models, Molecular; Molecular Structure; Mutation; Protein Kinase Inhibitors; Structure-Activity Relationship	2021
Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. Journal of medicinal chemistry, 2014, Oct-23, Volume: 57, Issue:20 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. Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Chemistry Techniques, Synthetic; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Inhibitory Concentration 50; Lung Neoplasms; Male; Mice; Middle Aged; Mutation; Protein Kinase Inhibitors; Rats, Inbred Strains; Xenograft Model Antitumor Assays	2014

Article

Year

Discovery and optimization of covalent EGFR T790M/L858R mutant inhibitors.

Bioorganic & medicinal chemistry letters, 2021, 11-15, Volume: 52

Epidermal growth factor receptor (EGFR) inhibitors have clinical utility in the treatment of non-small cell lung cancer (NSCLC) patients. Despite encouraging clinical efficacy with these agents, many patients develop resistance due to sensitizing (or activating) mutations ultimately leading to disease progression. In the majority of the cases, this resistance is due to the T790M mutation and frequently coexisting L858R. In addition, EGFR wild type receptor inhibition can lead to on target related dose limiting toxicities such as rash and diarrhea. We describe herein the identification of a mutant selective lead compound 12, an irreversible covalent inhibitor of EGFR T790M/L858R resistance mutations with selectivity over the wild type form. Significant tumor growth inhibition in preclinical models was observed with this lead.

Topics: Acrylamides; Afatinib; Aniline Compounds; Dose-Response Relationship, Drug; Drug Discovery; ErbB Receptors; Humans; Models, Molecular; Molecular Structure; Mutation; Protein Kinase Inhibitors; Structure-Activity Relationship

2021

Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor.

Journal of medicinal chemistry, 2014, Oct-23, Volume: 57, Issue:20

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.

Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Chemistry Techniques, Synthetic; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Inhibitory Concentration 50; Lung Neoplasms; Male; Mice; Middle Aged; Mutation; Protein Kinase Inhibitors; Rats, Inbred Strains; Xenograft Model Antitumor Assays

2014