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Your search keyword '"Misa Iwatani"' showing total 2 results
Start Over Author "Misa Iwatani" Publisher american chemical society
2 results on '"Misa Iwatani"'

1. Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1H)-one Derivatives as Orally eIF4A3-Selective Inhibitors

Author

Douglas R. Cary, Ryosuke Arai, Daisuke Morishita, Junpei Takeda, Shinobu Sasaki, Ryo Mizojiri, Sachio Shibata, Koichiro Fukuda, Misa Iwatani-Yoshihara, Mai Kosaka, Yohei Kosugi, Yoshihiko Satoh, Daisuke Nakata, Masahiro Kamaura, Kazuaki Takami, Yasuhiro Imaeda, and Shigekazu Sasaki

Subjects
0301 basic medicine, Stereochemistry, Organic Chemistry, Metabolic stability, Body weight, Biochemistry, Bioavailability, 03 medical and health sciences, Inhibitory potency, Piperazine, chemistry.chemical_compound, 030104 developmental biology, chemistry, In vivo, Drug Discovery, Molecule
Abstract

Starting from our previous eIF4A3-selective inhibitor 1a, a novel series of (piperazine-1-carbonyl)pyridin-2(1H)-one derivatives was designed, synthesized, and evaluated for identification of orally bioavailable probe molecules. Compounds 1o and 1q showed improved physicochemical and ADMET profiles, while maintaining potent and subtype-selective eIF4A3 inhibitory potency. In accord with their promising PK profiles and results from initial in vivo PD studies, compounds 1o and 1q showed antitumor efficacy with T/C values of 54% and 29%, respectively, without severe body weight loss. Thus, our novel series of compounds represents promising probe molecules for the in vivo pharmacological study of selective eIF4A3 inhibition.

Published
2017

2. Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2.

Author

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

Subjects
*RNA helicase, *SPLICEOSOMES, *ADENOSINE triphosphatase, *ALLOSTERIC regulation, *C-terminal binding proteins
Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2017
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