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6  úËõ Jan. 2014 Vol.27 No.1

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8  úËõ Jan. 2014 Vol.27 No.1

gìzq_Ëåwåw@ãw¤ÈÉÁ±³E­mail: yokoyoshmed.kobe­u.ac.jp
êåFªq¶¨w
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1991Nåãåwåw@w¤ÈmãúÛöC¹Cmiw)B¯N»w¤¤õB2004NPxõÈw¤Z
^[p¤£iåå·±i2006NÜÅj2004N»w¤d¤¤ZpJ­ºº·B2005NºÉ§§åwåw@¶½w¤ÈAgªìqõ³öB2008N»w¤d¤úËõÈw¤Z^[îÕ¤·B
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ÐªO_Ëåwåw@ãw¤ÈÉ³öCãw¤È·Éãw·E­mail: kataokapeople.kobe­u.ac.jp
êåFªq¶¨wmªðn
1977NåwãwãwÈ²ÆC1981Nåãåwåw@ãw¤ÈC¹iãwm)C1981NåãåwãwÉèC1985NÄR[hXvOn[o[¤É¤õC1986NÄn[o[hãÈåwÉAVX^gvtFbT[C1989
N_ËåwãwÉ³öC2001N_Ëå
wåw@ãw¤ÈÉ³öC2013N_Ëåwåw@ãw¤È·Éãw·Bðà ¡ ras ªñâ`qY¨ÌVK§Ì\¢îñðpµ½ªqWIªñ¡ÃòÌJ­Development of molecular targeted anti­cancer
drugs based on the information on a novel crystal
structure of the ras oncogene products
Fumi SHIMA1, Takashi KUMASAKA2, Shigeyuki MATSUMOTO1,
Yoko YOSHIKAWA1, Masaki YAMAMOTO3 and Tohru KATAOKA1
1Kobe University Graduate School of Medicine, 7_
5_1, Kusunoki, Chuo­ku, Kobe, 650_0017 Japan
2Japan Synchrotron Radiation Research Institute (SPring­8),

1_1_1, Kouto, Sayo­cho, Sayo­gun, Hyogo, 679_5198 Japan

3RIKEN SPring­8 Center, 1_
1_1, Kouto, Sayo­cho, Sayo­gun, Hyogo, 679_5148 Japan

Abstract

Mutational activation of the ras oncogene products, Ras proteins, is frequently observed in vari­
ous human cancers, making them promising anti­cancer drug targets. Despite vigorous eorts
made on the development of Ras inhibitors by many pharmaceutical companies, no eective ther­apeutic agents have been available to date. Our recent structural studies on Ras proteins unveiled
for the rst time that GTP­bound Ras proteins (Ras­GTP) undergo a dynamic transition betweendierent conformations, which results in formation of a drug­accessible surface pocket. Based on
this structural information on the novel pocket of Ras­GTP, we performed an in silico screening
followed by an in vitro screening for Ras inhibitors and succeeded in the discovery of the
Kobe0065_family compounds, which exhibited a potent anti_tumor activity in vivo. In this article,
we will describe the results of our study and its future prospects.

úËõ Jan. 2014 Vol.27 No.1  9