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Dive into the research topics where Hirotake Mizutani is active.

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Featured researches published by Hirotake Mizutani.


Nature | 2009

An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer

Teresa A. Soucy; Peter G. Smith; Michael Milhollen; Allison Berger; James M. Gavin; Sharmila Adhikari; James E. Brownell; Kristin E. Burke; David P. Cardin; Stephen Critchley; Courtney Cullis; Amanda Doucette; James J. Garnsey; Jeffrey L. Gaulin; Rachel E. Gershman; Anna R. Lublinsky; Alice McDonald; Hirotake Mizutani; Usha Narayanan; Edward J. Olhava; Stephane Peluso; Mansoureh Rezaei; Michael D. Sintchak; Tina Talreja; Michael Thomas; Tary Traore; Stepan Vyskocil; Jie Yu; Julie Zhang; Lawrence R. Dick

The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin–proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer.


Journal of Medicinal Chemistry | 2011

Design and Optimization of Potent and Orally Bioavailable Tetrahydronaphthalene Raf Inhibitors

Alexandra E. Gould; Ruth Adams; Sharmila Adhikari; Kathleen Aertgeerts; Roushan Afroze; Christopher Blackburn; Emily F. Calderwood; Ryan Chau; Jouhara Chouitar; Matthew O. Duffey; Dylan England; Cheryl A. Farrer; Nancy Forsyth; Khristofer Garcia; Jeffery Gaulin; Paul D. Greenspan; Ribo Guo; Sean Harrison; Shih-Chung Huang; Natalia Iartchouk; Dave Janowick; Mi-Sook Kim; Bheemashankar Kulkarni; Steven P. Langston; Jane X. Liu; Li-Ting Ma; Saurabh Menon; Hirotake Mizutani; Erin Paske; Christelle C. Renou

Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.


Archive | 2007

Heteroaryl compounds useful as inhibitors of E1 activating enzymes

Christopher F. Claiborne; Stephen Critchley; Steven P. Langston; Edward J. Olhava; Stephane Peluso; Stepan Vyskocil; Irache Visiers; Hirotake Mizutani; Courtney Cullis


Archive | 2014

PREPARATION OF AMINOTETRALIN COMPOUNDS

Alexandra E. Gould; Sean Harrison; Hirotake Mizutani; Ming Shen; Thomas E. Smyser; Stephen G. Stroud


Archive | 2010

Heteroaryls and their use as pi3k inhibitors

Hiroshi Banno; Masaaki Hirose; Osamu Kurasawa; Steven P. Langston; Hirotake Mizutani; Zhan Shi; Irache Visiers; Tricia J. Vos; Stepan Vyskocil


Archive | 2017

Heteroaryl compounds useful as inhibitors of sumo activating enzyme

Matthew O. Duffey; Dylan B. England; Scott Freeze; Zhigen Hu; Steven P. Langston; Charles Mcintyre; Hirotake Mizutani; Koji Ono; He Xu


Archive | 2008

Process for the synthesis of E1 activating enzyme inhibitors

Ian Armitage; Eric L. Elliott; Marianne Langston; Steven P. Langston; Quentin J. McCubbin; Hirotake Mizutani; Matthew Stirling; Lei Zhu


Archive | 2014

HETEROARYL INHIBITORS OF SUMO ACTIVATING ENZYME

Matthew O. Duffey; Dylan B. England; Zhigen Hu; Mitsuhiro Ito; Steven P. Langston; Charles Mcintyre; Hirotake Mizutani; He Xu


Archive | 2017

COMPUESTOS DE HETEROARILO ÚTILES COMO INHIBIDORES DE ENZIMA ACTIVADORA DE SUMO

He Xu; Koji Ono; Hirotake Mizutani; Charles Mintyre; Steven P. Langston; Zhigen Hu; Scott Freeze; Dylan England; Matthew O. Duffey


Archive | 2008

Process for the synthesis of intermediates compounds useful for the preparation of E1 activity activating enzyme inhibitors

Ian Armitage; Eric L. Elliot; Marianne Langston; Steven P. Langston; Quentin J. McCubbin; Hirotake Mizutani; Matthew Stirling; Lei Zhu

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Stepan Vyskocil

Millennium Pharmaceuticals

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Courtney Cullis

Millennium Pharmaceuticals

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Edward J. Olhava

Millennium Pharmaceuticals

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Irache Visiers

Millennium Pharmaceuticals

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Matthew O. Duffey

Millennium Pharmaceuticals

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Matthew Stirling

Millennium Pharmaceuticals

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Stephane Peluso

Millennium Pharmaceuticals

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Stephen Critchley

Millennium Pharmaceuticals

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