Keisuke Yamamoto - Academia.edu (original) (raw)

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Papers by Keisuke Yamamoto

Research paper thumbnail of Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold

Bioorganic & Medicinal Chemistry, 2019

We previously identified dibenzooxepine derivative 1 as a potent PPARγ ligand with a unique bindi... more We previously identified dibenzooxepine derivative 1 as a potent PPARγ ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPARγ activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-a]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPARγ ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.

Research paper thumbnail of Discovery of Tofogliflozin, a Novel C-Arylglucoside with an O-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Journal of Medicinal Chemistry, 2012

The structures of three hit compounds from CSD search: S2 CYP3A4 inhibition data for TDI: S3 X-ra... more The structures of three hit compounds from CSD search: S2 CYP3A4 inhibition data for TDI: S3 X-ray crystallographic data of 17: S6 In vitro chemical and metabolic stability data of tofogliflozin: S10

Research paper thumbnail of Optimal Synthetic Glycosylation of a Therapeutic Antibody

Angewandte Chemie (International ed. in English), Jan 12, 2016

Glycosylation patterns in antibodies critically determine biological and physical properties but ... more Glycosylation patterns in antibodies critically determine biological and physical properties but their precise control is a significant challenge in biology and biotechnology. We describe herein the optimization of an endoglycosidase-catalyzed glycosylation of the best-selling biotherapeutic Herceptin, an anti-HER2 antibody. Precise MS analysis of the intact four-chain Ab heteromultimer reveals nonspecific, non-enzymatic reactions (glycation), which are not detected under standard denaturing conditions. This competing reaction, which has hitherto been underestimated as a source of side products, can now be minimized. Optimization allowed access to the purest natural form of Herceptin to date (≥90 %). Moreover, through the use of a small library of sugars containing non-natural functional groups, Ab variants containing defined numbers of selectively addressable chemical tags (reaction handles at Sia C1) in specific positions (for attachment of cargo molecules or "glycorandomizat...

Research paper thumbnail of An Endoglycosidase with Alternative Glycan Specificity Allows Broadened Glycoprotein Remodelling

Journal of the American Chemical Society, 2012

Protein endoglycosidases are useful for biocatalytic alteration of glycans on protein surfaces, b... more Protein endoglycosidases are useful for biocatalytic alteration of glycans on protein surfaces, but the currently limited selectivity of endoglycosidases has prevented effective manipulation of certain N-linked glycans widely found in nature. Here we reveal that a bacterial endoglycosidase from Streptococcus pyogenes, EndoS, is complementary to other known endoglycosidases (EndoA, EndoH) used for current protein remodeling. It allows processing of complex-type N-linked glycans +/− core fucosylation but does not process oligomannose-or hybrid-type glycans. This biocatalytic activity now addresses previously refractory antibody glycoforms.

Research paper thumbnail of Creation of an α-Mannosynthase from a Broad Glycosidase Scaffold

Angewandte Chemie International Edition, 2012

Research paper thumbnail of Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold

Bioorganic & Medicinal Chemistry, 2019

We previously identified dibenzooxepine derivative 1 as a potent PPARγ ligand with a unique bindi... more We previously identified dibenzooxepine derivative 1 as a potent PPARγ ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPARγ activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-a]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPARγ ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.

Research paper thumbnail of Discovery of Tofogliflozin, a Novel C-Arylglucoside with an O-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

Journal of Medicinal Chemistry, 2012

The structures of three hit compounds from CSD search: S2 CYP3A4 inhibition data for TDI: S3 X-ra... more The structures of three hit compounds from CSD search: S2 CYP3A4 inhibition data for TDI: S3 X-ray crystallographic data of 17: S6 In vitro chemical and metabolic stability data of tofogliflozin: S10

Research paper thumbnail of Optimal Synthetic Glycosylation of a Therapeutic Antibody

Angewandte Chemie (International ed. in English), Jan 12, 2016

Glycosylation patterns in antibodies critically determine biological and physical properties but ... more Glycosylation patterns in antibodies critically determine biological and physical properties but their precise control is a significant challenge in biology and biotechnology. We describe herein the optimization of an endoglycosidase-catalyzed glycosylation of the best-selling biotherapeutic Herceptin, an anti-HER2 antibody. Precise MS analysis of the intact four-chain Ab heteromultimer reveals nonspecific, non-enzymatic reactions (glycation), which are not detected under standard denaturing conditions. This competing reaction, which has hitherto been underestimated as a source of side products, can now be minimized. Optimization allowed access to the purest natural form of Herceptin to date (≥90 %). Moreover, through the use of a small library of sugars containing non-natural functional groups, Ab variants containing defined numbers of selectively addressable chemical tags (reaction handles at Sia C1) in specific positions (for attachment of cargo molecules or "glycorandomizat...

Research paper thumbnail of An Endoglycosidase with Alternative Glycan Specificity Allows Broadened Glycoprotein Remodelling

Journal of the American Chemical Society, 2012

Protein endoglycosidases are useful for biocatalytic alteration of glycans on protein surfaces, b... more Protein endoglycosidases are useful for biocatalytic alteration of glycans on protein surfaces, but the currently limited selectivity of endoglycosidases has prevented effective manipulation of certain N-linked glycans widely found in nature. Here we reveal that a bacterial endoglycosidase from Streptococcus pyogenes, EndoS, is complementary to other known endoglycosidases (EndoA, EndoH) used for current protein remodeling. It allows processing of complex-type N-linked glycans +/− core fucosylation but does not process oligomannose-or hybrid-type glycans. This biocatalytic activity now addresses previously refractory antibody glycoforms.

Research paper thumbnail of Creation of an α-Mannosynthase from a Broad Glycosidase Scaffold

Angewandte Chemie International Edition, 2012