公开(公告)号：US20060111329A1

公开(公告)日：2006-05-25

申请号：US11275662

申请日：2006-01-23

申请人： Seth Rose ,  Scott Lefler ,  Steven Ottersberg ,  Ann Kim ,  Karl Okolotowicz ,  Rosemarie Hartman

发明人： Seth Rose ,  Scott Lefler ,  Steven Ottersberg ,  Ann Kim ,  Karl Okolotowicz ,  Rosemarie Hartman

IPC分类号： A61K31/66 ,  C07F9/02 ,  C07C67/02 ,  C07D233/61

CPC分类号： A61K31/66 ,  A61K31/20 ,  C07C69/63 ,  C07C217/46 ,  C07C219/20 ,  C07D303/32 ,  C07D303/48 ,  C07F9/091

摘要： Oncoproteins such as Ras and RhoB are known to induce cell division in an unrestrained manner when such proteins are localized at the inner surface of a cancer cell membrane. The localization is effected by the prenylation reaction, whereby a hydrophobic group (e.g. a farnesyl group) is attached to the protein in the presence of an enzyme (e.g. farnesyl protein transferase). Deactivation of the prenylation enzyme through covalent modification can therefore ultimately result in the mitigation and/or cessation of cancer cell growth. Various prenylation inhibitors having the necessary structural groups to bond covalently, or essentially irreversibly, to the prenylation enzyme include carbonyl or thiocarbonyl compounds (or masked versions of these compounds) and alpha oxo-epoxides bonded to a hydrophobic, substrate-mimicking group. The carbonyl or thiocarbonyl compounds also contain a nucleofugal atom or group to enhance the tendency to form covalent bonds.

摘要翻译： 已知当诸如Ras和RhoB的癌蛋白定位在癌细胞膜的内表面时，诸如Ras和RhoB的癌蛋白以无限制的方式诱导细胞分裂。 定位通过异戊烯化反应进行，由此在酶（例如法呢基蛋白转移酶）的存在下将疏水基团（例如法呢基）连接到蛋白质上。 因此，通过共价修饰来停用异戊烯基化酶可最终导致癌细胞生长的缓解和/或停止。 具有与异戊烯基化酶共价或基本上不可逆地键合的必需结构基团的各种异戊二烯基化抑制剂包括与疏水性底物模拟基团键合的羰基或硫代羰基化合物（或这些化合物的掩蔽型）和α氧代环氧化物。 羰基或硫代羰基化合物还含有核原子或基团以增强形成共价键的倾向。

公开(公告)号：US07012097B2

公开(公告)日：2006-03-14

申请号：US10437050

申请日：2003-05-14

申请人： Seth D. Rose ,  Steven R. Ottersberg ,  Karl J. Okolotowicz ,  Dale E. Robinson ,  Rosemarie Hartman ,  Scott Lefler

发明人： Seth D. Rose ,  Steven R. Ottersberg ,  Karl J. Okolotowicz ,  Dale E. Robinson ,  Rosemarie Hartman ,  Scott Lefler

IPC分类号： A01N37/12

CPC分类号： C12Q1/48 ,  A61K31/12 ,  A61K31/121 ,  A61K31/195 ,  C12N9/1085 ,  C12N9/99 ,  C12Y205/01029 ,  G01N2500/04

摘要： Prenylating enzymes are involved in modifying oncoproteins, such as RAS, so that growth of neoplastic cells becomes uncontrolled. Inactivation of such enzymes can prevent uncontrolled growth. α-Dicarbonyl compounds can be used to covalently modify and thereby inactivate prenylating enzymes such as protein farnesyltransferase and protein geranylgeranyltransferase. The compounds can be designed to enhance affinity and/or specificity for a particular protein substrate.

公开(公告)号：US20060030624A1

公开(公告)日：2006-02-09

申请号：US11246259

申请日：2005-10-11

申请人： Seth Rose ,  Steven Ottersberg ,  Karl Okolotowicz ,  Dale Robinson ,  Rosemarie Hartman ,  Scott Lefler

发明人： Seth Rose ,  Steven Ottersberg ,  Karl Okolotowicz ,  Dale Robinson ,  Rosemarie Hartman ,  Scott Lefler

IPC分类号： A61K31/195

CPC分类号： C12Q1/48 ,  A61K31/12 ,  A61K31/121 ,  A61K31/195 ,  C12N9/1085 ,  C12N9/99 ,  C12Y205/01029 ,  G01N2500/04

摘要： Prenylating enzymes are involved in modifying oncoproteins, such as RAS, so that growth of neoplastic cells becomes uncontrolled. Inactivation of such enzymes can prevent uncontrolled growth. α-Dicarbonyl compounds can be used to covalently modify and thereby inactivate prenylating enzymes such as protein farnesyltransferase and protein geranylgeranyltransferase. The compounds can be designed to enhance affinity and/or specificity for a particular protein substrate.

公开(公告)号：US07344851B2

公开(公告)日：2008-03-18

申请号：US11246259

申请日：2005-10-11

申请人： Seth D. Rose ,  Steven R. Ottersberg ,  Karl J. Okolotowicz ,  Dale E. Robinson ,  Rosemarie F. Hartman ,  Scott Lefler

发明人： Seth D. Rose ,  Steven R. Ottersberg ,  Karl J. Okolotowicz ,  Dale E. Robinson ,  Rosemarie F. Hartman ,  Scott Lefler

IPC分类号： C12Q1/48

CPC分类号： C12Q1/48 ,  A61K31/12 ,  A61K31/121 ,  A61K31/195 ,  C12N9/1085 ,  C12N9/99 ,  C12Y205/01029 ,  G01N2500/04

摘要： Prenylating enzymes are involved in modifying oncoproteins, such as RAS, so that growth of neoplastic cells becomes uncontrolled. Inactivation of such enzymes can prevent uncontrolled growth. α-Dicarbonyl compounds can be used to covalently modify and thereby inactivate prenylating enzymes such as protein farnesyltransferase and protein geranylgeranyltransferase. The compounds can be designed to enhance affinity and/or specificity for a particular protein substrate.

摘要翻译： 过氧化酶参与修饰癌蛋白，如RAS，使肿瘤细胞的生长变得不受控制。 这种酶的失活可以防止不受控制的生长。 α-二羰基化合物可用于共价修饰，从而使预活化酶失活，如蛋白法呢基转移酶和蛋白质香叶基香叶基转移酶。 化合物可被设计成增强特定蛋白质底物的亲和性和/或特异性。

公开(公告)号：US06576436B1

公开(公告)日：2003-06-10

申请号：US09457476

申请日：1999-12-09

申请人： Seth D. Rose ,  Steven R. Ottersberg ,  Karl J. Okolotowicz ,  Dale E. Robinson ,  Rosemarie Hartman ,  Scott Lefler

发明人： Seth D. Rose ,  Steven R. Ottersberg ,  Karl J. Okolotowicz ,  Dale E. Robinson ,  Rosemarie Hartman ,  Scott Lefler

IPC分类号： C12Q148

CPC分类号： C12Q1/48 ,  A61K31/12 ,  A61K31/121 ,  A61K31/195 ,  C12N9/1085 ,  C12N9/99 ,  C12Y205/01029 ,  G01N2500/04

摘要： Prenylating enzymes are involved in modifying oncoproteins, such as RAS, so that growth of neoplastic cells becomes uncontrolled. Inactivation of such enzymes can prevent uncontrolled growth. &agr;-Dicarbonyl compounds can be used to covalently modify and thereby inactivate prenylating enzymes such as protein farnesyltransferase and protein geranylgeranyltransferase. The compounds can be designed to enhance affinity and/or specificity for a particular protein substrate.

摘要翻译： 过氧化酶参与修饰癌蛋白，如RAS，使肿瘤细胞的生长变得不受控制。 这种酶的失活可以防止不受控制的生长。 α-二羰基化合物可用于共价修饰，从而使预活化酶失活，如蛋白法呢基转移酶和蛋白质香叶基香叶基转移酶。 化合物可被设计成增强特定蛋白质底物的亲和性和/或特异性。