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Dive into the research topics where Kazuko Yonemori is active.

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Featured researches published by Kazuko Yonemori.


Journal of Medicinal Chemistry | 2017

Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2

Misa Iwatani-Yoshihara; Masahiro Ito; Michael G. Klein; Takeshi Yamamoto; Kazuko Yonemori; Toshio Tanaka; Masanori Miwa; Daisuke Morishita; Satoshi Endo; Richard Tjhen; Ling Qin; Atsushi Nakanishi; Hironobu Maezaki; Tomohiro Kawamoto

Brr2 is an RNA helicase belonging to the Ski2-like subfamily and an essential component of spliceosome. Brr2 catalyzes an ATP-dependent unwinding of the U4/U6 RNA duplex, which is a critical step for spliceosomal activation. An HTS campaign using an RNA-dependent ATPase assay and initial SAR study identified two different Brr2 inhibitors, 3 and 12. Cocrystal structures revealed 3 binds to an unexpected allosteric site between the C-terminal and the N-terminal helicase cassettes, while 12 binds an RNA-binding site inside the N-terminal cassette. Selectivity profiling indicated the allosteric inhibitor 3 is more Brr2-selective than the RNA site binder 12. Chemical optimization of 3 using SBDD culminated in the discovery of the potent and selective Brr2 inhibitor 9 with helicase inhibitory activity. Our findings demonstrate an effective strategy to explore selective inhibitors for helicases, and 9 could be a promising starting point for exploring molecular probes to elucidate biological functions and the therapeutic relevance of Brr2.


Bioorganic & Medicinal Chemistry Letters | 2017

Investigation of the structural requirements of K-Ras(G12D) selective inhibitory peptide KRpep-2d using alanine scans and cysteine bridging

Ayumu Niida; Shigekazu Sasaki; Kazuko Yonemori; Tomoya Sameshima; Masahiro Yaguchi; Taiji Asami; Kotaro Sakamoto; Masahiro Kamaura

A structure-activity relationship study of a K-Ras(G12D) selective inhibitory cyclic peptide, KRpep-2d was performed. Alanine scanning of KRpep-2d focusing on the cyclic moiety showed that Leu7, Ile9, and Asp12 are the key elements for K-Ras(G12D) selective inhibition of KRpep-2d. The cysteine bridging was also examined to identify the stable analog of KRpep-2d under reductive conditions. As a result, the KRpep-2d analog (12) including mono-methylene bridging showed potent K-Ras(G12D) selective inhibition in both the presence and the absence of dithiothreitol. This means that mono-methylene bridging is an effective strategy to obtain a reduction-resistance analog of parent disulfide cyclic peptides. Peptide 12 inhibited proliferation of K-Ras(G12D)-driven cancer cells significantly. These results gave valuable information for further optimization of KRpep-2d to provide novel anti-cancer drug candidates targeting the K-Ras(G12D) mutant.


Biochemical and Biophysical Research Communications | 2017

Identification of PARP14 inhibitors using novel methods for detecting auto-ribosylation

Mariko Yoneyama-Hirozane; Shin-ichi Matsumoto; Yukio Toyoda; Kumar Singh Saikatendu; Yumi Zama; Kazuko Yonemori; Motomi Oonishi; Tsuyoshi Ishii; Tomohiro Kawamoto

Poly(ADP-ribose) polymerases (PARPs) use nicotinamide adenine dinucleotide (NAD+) as a co-substrate to transfer ADP-ribose when it releases nicotinamide as the metabolized product. Enzymes of the PARP family play key roles in detecting and repairing DNA, modifying chromatin, regulating transcription, controlling energy metabolism, and inducing cell death. PARP14, the original member of the PARP family, has been reported to be associated with the development of inflammatory diseases and various cancer types, making it a potential therapeutic target. In this study, we purified the macrodomain-containing PARP14 enzyme and established an assay for detecting the auto-ribosylation activity of PARP14 using RapidFire high-throughput mass spectrometry and immunoradiometric assay using [3H]NAD+. Subsequently, we performed high-throughput screening using the assays and identified small-molecule hit compounds, which showed NAD+-competitive and PARP14-selective inhibitory activities. Co-crystal structures of PARP14 with certain hit compounds revealed that the inhibitors bind to the NAD+-binding site. Finally, we confirmed that the hit compounds interacted with intracellular PARP14 by a cell-based protein stabilization assay. Thus, we successfully identified primary candidate compounds for further investigation.


ACS Medicinal Chemistry Letters | 2017

Crystal Structure of a Human K-Ras G12D Mutant in Complex with GDP and the Cyclic Inhibitory Peptide KRpep-2d

Satoshi Sogabe; Yusuke Kamada; Masanori Miwa; Ayumu Niida; Tomoya Sameshima; Masahiro Kamaura; Kazuko Yonemori; Shigekazu Sasaki; Junichi Sakamoto; Kotaro Sakamoto

The Ras proteins play roles in cell differentiation, proliferation, and survival. Aberrant signaling through Ras-mediated pathways in tumor cells occurs as a result of several types of mutational damage, which most frequently affects the amino acids G12, G13, and Q61. Recently, KRpep-2d was identified as a K-Ras(G12D) selective inhibitory peptide against the G12D mutant of K-Ras, which is a key member of the Ras protein family and an attractive cancer therapeutic target. In this study, the crystal structure of the human K-Ras(G12D) mutant was determined in complex with GDP and KRpep-2d at 1.25 Å resolution. This structure revealed that the peptide binds near Switch II and allosterically blocks protein-protein interactions with the guanine nucleotide exchange factor. This discovery of a unique binding pocket provides valuable information that will facilitate the design of direct Ras inhibitors.


Bioorganic & Medicinal Chemistry | 2017

Identification of novel quinazolinedione derivatives as RORγt inverse agonist

Yoshiyuki Fukase; Ayumu Sato; Yoshihide Tomata; Atsuko Ochida; Mitsunori Kono; Kazuko Yonemori; Keiko Koga; Toshitake Okui; Masashi Yamasaki; Yasushi Fujitani; Hideyuki Nakagawa; Ryoukichi Koyama; Masaharu Nakayama; Robert J. Skene; Bi-Ching Sang; Isaac D. Hoffman; Junya Shirai; Satoshi Yamamoto

Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed.


Bioorganic & Medicinal Chemistry | 2017

Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19 dual inhibitors and elimination of their CYP3A4 time-dependent inhibition potential

Jun Fujimoto; Takaharu Hirayama; Yasuhiro Hirata; Yukiko Hikichi; Saomi Murai; Maki Hasegawa; Yuka Hasegawa; Kazuko Yonemori; Akito Hata; Kazunobu Aoyama; Douglas R. Cary

In this article, synthetic studies around a pyridylacrylamide-based hit compound (1), utilizing structure-based drug design guided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was conducted aiming an interaction with the proximal amino acids, and then replacement of the morpholine ring was targeted for decreasing potential of time-dependent CYP3A4 inhibition. These efforts led to the compound 4k, with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4 inhibition (CDK8 IC50: 2.5nM; CYP3A4 TDI: 99% compound remaining). Compound 4k was found to possess a highly selective kinase inhibition profile, and also showed favorable pharmacokinetic profile. Oral administration of 4k (15mg/kg, bid. for 2weeks) suppressed tumor growth (T/C 29%) in an RPMI8226 mouse xenograft model.


Bioorganic & Medicinal Chemistry | 2018

Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents

Takuto Kojima; Yasutomi Asano; Osamu Kurasawa; Yasuhiro Hirata; Naoki Iwamura; Tzu-Tshin Wong; Bunnai Saito; Yuta Tanaka; Ryosuke Arai; Kazuko Yonemori; Yasufumi Miyamoto; Yoji Sagiya; Masahiro Yaguchi; Sachio Shibata; Akio Mizutani; Osamu Sano; Ryutaro Adachi; Yoshinori Satomi; Megumi Hirayama; Kazunobu Aoyama; Yuto Hiura; Atsushi Kiba; Shuji Kitamura; Shinichi Imamura

We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics.


Bioorganic & Medicinal Chemistry | 2018

Discovery of orally efficacious RORγt inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds

Junya Shirai; Yoshihide Tomata; Mitsunori Kono; Atsuko Ochida; Yoshiyuki Fukase; Ayumu Sato; Shinichi Masada; Tetsuji Kawamoto; Kazuko Yonemori; Ryoukichi Koyama; Hideyuki Nakagawa; Masaharu Nakayama; Keiko Uga; Akira Shibata; Keiko Koga; Toshitake Okui; Mikio Shirasaki; Robert J. Skene; Bi-Ching Sang; Isaac D. Hoffman; Wes Lane; Yasushi Fujitani; Masashi Yamasaki; Satoshi Yamamoto

A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.


Bioorganic & Medicinal Chemistry | 2017

Design and synthesis of selective CDK8/19 dual inhibitors: Discovery of 4,5-dihydrothieno[3',4':3,4]benzo[1,2-d]isothiazole derivatives

Koji Ono; Hiroshi Banno; Masanori Okaniwa; Takaharu Hirayama; Naoki Iwamura; Yukiko Hikichi; Saomi Murai; Maki Hasegawa; Yuka Hasegawa; Kazuko Yonemori; Akito Hata; Kazunobu Aoyama; Douglas R. Cary


Bioorganic & Medicinal Chemistry | 2017

Discovery of Novel and Potent Stearoyl Coenzyme A Desaturase 1 (SCD1) Inhibitors as Anticancer Agents

Keisuke Imamura; Naoki Tomita; Youichi Kawakita; Yoshiteru Ito; Kouji Ono; Noriyuki Nii; Tohru Miyazaki; Kazuko Yonemori; Michiko Tawada; Hiroyuki Sumi; Yoshihiko Satoh; Yukiko Yamamoto; Ikuo Miyahisa; Masako Sasaki; Yoshinori Satomi; Megumi Hirayama; Ryuichi Nishigaki; Hironobu Maezaki

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Atsuko Ochida

Takeda Pharmaceutical Company

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Hideyuki Nakagawa

Takeda Pharmaceutical Company

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Junya Shirai

Takeda Pharmaceutical Company

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Satoshi Yamamoto

Takeda Pharmaceutical Company

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Yoshiyuki Fukase

Takeda Pharmaceutical Company

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Ayumu Sato

Takeda Pharmaceutical Company

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Bi-Ching Sang

Takeda Pharmaceutical Company

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Isaac D. Hoffman

Takeda Pharmaceutical Company

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Kazunobu Aoyama

Takeda Pharmaceutical Company

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Masashi Yamasaki

Takeda Pharmaceutical Company

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