ABSTRACT
The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Herein, we describe the discovery of the 2,4-diaminonicotinamide derivative 5j, which shows potent inhibitory activity against EGFR del19/T790M/C797S and L858R/T790M/C797S. We also report the structure-activity relationship of the 2,4-diaminonicotinamide derivatives and the co-crystal structure of 5j and EGFR del19/T790M/C797S.
Subject(s)
ErbB Receptors , Lung Neoplasms , Niacinamide , Humans , Drug Resistance, Neoplasm , ErbB Receptors/drug effects , ErbB Receptors/genetics , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , /pharmacology , Niacinamide/analogs & derivatives , Niacinamide/chemistryABSTRACT
Fibrolamellar hepatocellular carcinoma (FL-HCC) is known as a highly aggressive liver cancer that typically affects young adults without virus infection. Since this type of cancer does not respond to chemotherapy, surgery is the only known effective therapeutic option. Most FL-HCC patients express the fusion gene DNAJB1-PRKACA, which has been recognized as the signature of FL-HCC. It has also been reported that PRKACA kinase activity is essential for its oncogenic activity, suggesting that PRKACA kinase inhibition could be considered as an useful therapeutic target. In this study, we established an evaluation system for PRKACA kinase inhibitors and synthesized DS89002333, a novel PRKACA inhibitor. DS89002333 showed potent PRKACA inhibitory activity and inhibited fusion protein-dependent cell growth both in vitro and in vivo. Furthermore, this compound showed anti-tumor activity in an FL-HCC patient-derived xenograft model expressing the DNAJB1-PRKACA fusion gene. Our data suggest that DS89002333 could be considered as a potential therapeutic agent for FL-HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Catalytic Domain , Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics , Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/metabolism , Gene Expression Regulation, Neoplastic , HSP40 Heat-Shock Proteins/genetics , HSP40 Heat-Shock Proteins/metabolism , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Protein Kinase Inhibitors , Young AdultABSTRACT
A detailed description of our second-generation total synthesis of salinosporamide A is presented. Three contiguous stereocenters in the γ-lactam structure seen in the natural product were established by stereoselective functionalization of a D-arabinose scaffold, including an Overman rearrangement to generate a highly congested tetrasubstituted carbon center. One of the definitive reactions in the synthesis was a Lewis acid mediated skeletal rearrangement of a pyranose structure, which enabled the practical conversion of the carbohydrate scaffold to the γ-lactam structure embedded in salinosporamide A. The use of a benzyl ester as a protective group for a sterically hindered carboxylic acid led to a one-pot global deprotection at the end of the synthesis.
