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【drug-news】Gleevc 修饰,可以消除其副作用?
03 December 2007
Scientists in the US have used a new drug design strategy to remove the cardiac side-effects of a popular cancer drug. The approach could help make other cancer treatments safer, researchers say.
Imatinib, marketed as Glivec in Europe and Gleevec in the US, has been used to treat myeloid leukaemia (CML) and gastrointestinal stromal tumor (GIST) since 2001. The drug targets proteins called tyrosine kinases that are involved in cell reproduction. In GIST, one class of these proteins - the KIT kinases - can become permanently 'switched on', making cells divide uncontrollably.
The modified imatinib molecule: WBZ_4. The added methyl group is shown in red
© Fernández et al, J. Clin. Invest
But imatinib is known to cause heart problems in some people because it also switches off tyrosine kinases in the ABL family. Now three teams working together at Rice University and the M. D. Anderson Cancer Center in Houston, Texas, have redesigned imatinib so that it only inhibits KIT kinases - and not ones in the ABL family.
The team used a novel insight to design the compound - examining how water molecules detach and attach from the drug targets. These 'de-wetting' differences helped the team to identify how best to make modifications to imatinib's structure. By adding a methyl group at a critical point, they made a new compound named WBZ_4 that inhibited KIT kinases - but not those from the ABL family.
In addition, WBZ_4 also inhibited JNK tyrosine kinases - an effect that is known to further protect the heart. The team then conducted mouse studies on the new drug and showed that WBZ_4 maintained the anticancer activity of imatinib but is less cardiotoxic.
Imatinib (top) binds to both KIT and ABL kinases. Imatinib was redesigned to produce WBZ_4 (bottom) which binds to KIT and additionally JNK kinases, but not ABL.
© Fernández et al, J. Clin. Invest
'The approach used here holds great promise to allow more customized development of rationally designed therapeutic agents,' commented George Demetri at the Dana-Farber Cancer Institute, Boston.
Thomas Force, at the Center for Translational Medicine at Thomas Jefferson University, US, has studied imatinib. 'The biggest message of this paper is that a cardiotoxic cause can be identified and steered away from,' Force told Chemistry World. 'There are hundreds of agents in development that could benefit from this research.'
Lewis Brindley 本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领。 Cancer drug gets a makeover
抗癌药物面貌改变
03 December 2007
2007年12月3日
Scientists in the US have used a new drug design strategy to remove the cardiac side-effects of a popular cancer drug. The approach could help make other cancer treatments safer, researchers say.
美国的科学家使用了一种新的药物设计策略，以消除热门的抗癌药物对心脏产生的副作用。该方法可以帮助其他癌症疗法更安全，研究人员说。
Imatinib, marketed as Glivec in Europe and Gleevec in the US, has been used to treat myeloid leukaemia (CML) and gastrointestinal stromal tumor (GIST) since 2001. The drug targets proteins called tyrosine kinases that are involved in cell reproduction. In GIST, one class of these proteins - the KIT kinases - can become permanently 'switched on', making cells divide uncontrollably.
Imatinib，在欧洲和在美国伊马替尼市场上称为Glive c，自2001年以来已被用来治疗骨髓性白血病（慢性骨髓性白血病）和胃肠道间质肿瘤（GIST）。该药物靶蛋白名为酪氨酸激酶，作用是参与细胞复制。在GIST中的一类蛋白质- KIT激酶-可以成为永久'接通'，使细胞分裂失控。
The modified imatinib molecule: WBZ_4. The added methyl group is shown in red
改良的imatinib分子： wbz_4 ，加上甲基组是表现为红色
© Fernández et al, J. Clin. Invest
But imatinib is known to cause heart problems in some people because it also switches off tyrosine kinases in the ABL family. Now three teams working together at Rice University and the M. D. Anderson Cancer Center in Houston, Texas, have redesigned imatinib so that it only inhibits KIT kinases - and not ones in the ABL family.
但众所周知imatinib在一些人中可导致心脏问题，因为它还要开关ABL家族的酪氨酸激酶。现在，三个小组共同工作在赖斯大学与得克萨斯州休斯敦市的M. D. Anderson癌症中心，重新设计imatinib，以使它只抑制KIT激酶-而非ABL家族的酪氨酸激酶。
The team used a novel insight to design the compound - examining how water molecules detach and attach from the drug targets. These 'de-wetting' differences helped the team to identify how best to make modifications to imatinib's structure. By adding a methyl group at a critical point, they made a new compound named WBZ_4 that inhibited KIT kinases - but not those from the ABL family.
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作者:admin@医学,生命科学 2011-08-23 05:14
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