Patents by Inventor Anthony E. Pegg
Anthony E. Pegg has filed for patents to protect the following inventions. This listing includes patent applications that are pending as well as patents that have already been granted by the United States Patent and Trademark Office (USPTO).
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Patent number: 8637485Abstract: The crystal structure of the complex of S-adenosylmethionine methyl ester with h?doMetDC F223A, a mutant where the stacking of the aromatic rings of F7, adenine and F223 would be eliminated. The structure of this mutant with the ester shows that the ligand still maintains a syn conformation aided by pi-pi interactions to F7, hydrogen bonds to the backbone of Glu67, and electrostatic interactions. Several series of AdoMet substrate analogues with a variety of substituents at the 8 position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. To understand these results, virtual modeling of the enzyme inhibitor complexes and the crystal structures of human AdoMetDC with 5?-deoxy-5?-[N-methyl-N-[2-(aminooxy)ethyl]amino-8-methyl]adenosine (MAOEMA) and 5?-deoxy-5?-[N-methyl-N-[4-(aminooxy)butyl]amino-8-ethyl]adenosine (MAOBEA) at the active site have been determined experimentally.Type: GrantFiled: August 1, 2008Date of Patent: January 28, 2014Assignees: Southern Research Institute, Cornell University, H. Lee Moffitt Cancer and Research Institute, The Penn State Research FoundationInventors: John A. Secrist, III, Steven Ealick, Shridhar Bale, Anthony E. Pegg, Diane E. McCloskey, Wayne C. Guida
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Patent number: 8188055Abstract: Disclosed are compounds that are AGT inactivators that include a folate residue, e.g., a compound of formula (I), wherein X1, X2, R1, and R2 are as described herein. Also disclosed is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. Also disclosed are methods of enhancing the chemotherapeutic treatment of tumor cells and inactivating AGT in a tumor cell. The methods comprise, inter alia, administering a compound or pharmaceutically acceptable salt of formula (I).Type: GrantFiled: March 12, 2008Date of Patent: May 29, 2012Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services, The Penn State Research FoundationInventors: Robert C. Moschel, Matthew Karl Moschel, legal representative, Anthony E. Pegg, Sahar Javanmard, Natalia Loktionova, Gary Pauly
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Publication number: 20110009354Abstract: The crystal structure of the complex of S-adenosylmethionine methyl ester with h?doMetDC F223A, a mutant where the stacking of the aromatic rings of F7, adenine and F223 would be eliminated. The structure of this mutant with the ester shows that the ligand still maintains a syn conformation aided by pi-pi interactions to F7, hydrogen bonds to the backbone of Glu67, and electrostatic interactions. Several series of AdoMet substrate analogues with a variety of substituents at the 8 position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. To understand these results, virtual modeling of the enzyme inhibitor complexes and the crystal structures of human AdoMetDC with 5?-deoxy-5?-[N-methyl-N-[2-(aminooxy)ethyl]amino-8-methyl]adenosine (MAOEMA) and 5?-deoxy-5?-[N-methyl-N-[4-(aminooxy)butyl]amino-8-ethyl]adenosine (MAOBEA) at the active site have been determined experimentally.Type: ApplicationFiled: August 1, 2008Publication date: January 13, 2011Inventors: John A. Secrist, III, Steve Ealick, Shridhar Bale, Anthony E. Pegg, Diane E. McCloskey, Wayne C. Guida
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Patent number: 7825096Abstract: Disclosed are prodrugs of inactivators of O6-alkylguanine-DNA alkyltransferase (AGT). The prodrugs are cleavable by the ?-glucuronidase enzyme, which is either administered to the patient or produced by necrotic tumor cells. The prodrugs are represented by the formula A-B-C, wherein A is a glucuronosyl residue linked through its 1-oxygen to the phenyl ring of B; B is a benzyloxycarbonyl group, optionally ring-substituted with one or more electron withdrawing groups; and C is an inactivator of AGT, e.g., a substituted or unsubstituted O6-benzylguanine or O6-benzyl-2?-deoxyguanosine. Also disclosed are additional inactivators of AGT, pharmaceutical compositions comprising an inactivator or prodrug and a pharmaceutically acceptable carrier, and a method of use of the inactivator or prodrug in enhancing the chemotherapeutic treatment of tumor cells in a mammal, e.g., a human, with an antineoplastic alkylating agent that causes cytotoxic lesions at the O6-position of guanine.Type: GrantFiled: March 7, 2007Date of Patent: November 2, 2010Assignees: The United States of America as represented by the Department of Health and Human Services, The Penn State Research FoundationInventors: Robert C. Moschel, Matthew Karl Moschel, legal representative, Natalia A. Loktionova, Anthony E. Pegg, Gary T. Pauly
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Publication number: 20100204172Abstract: Disclosed are compounds that are AGT inactivators that include a folate residue, e.g., a compound of formula (I), wherein X1, X2, R1, and R2 are as described herein. Also disclosed is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. Also disclosed are methods of enhancing the chemotherapeutic treatment of tumor cells and inactivating AGT in a tumor cell. The methods comprise, inter alia, administering a compound or pharmaceutically acceptable salt of formula (I).Type: ApplicationFiled: March 12, 2008Publication date: August 12, 2010Applicants: Department of Health and Human Services, The Penn State Research FoundationInventors: Robert C. Moschel, Anthony E. Pegg, Sahar Javanmard, Natalia Loktionova, Gary Pauly
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Patent number: 6436945Abstract: The present invention provides AGT inactivating compounds, for example, substituted O6-benzyl-8-aza-guanines of the formula wherein R, for example, is pivaloyloxymethyl as well as pharmaceutical compositions comprising such compounds along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O6-position of guanine, by administering to a mammal an effective amount of one of the aforesaid compounds, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O6-position of guanine.Type: GrantFiled: August 14, 2001Date of Patent: August 20, 2002Assignees: The United States of America as represented by the of Health and Human Services, The Penn State Research Foundation, Arch Development CorporationInventors: Robert C. Moschel, Anthony E. Pegg, M. Eileen Dolan, Mi-Young Chae
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Publication number: 20020013299Abstract: The present invention provides AGT inactivating compounds such as substituted O6-benzylguanines of the formula 1Type: ApplicationFiled: August 14, 2001Publication date: January 31, 2002Applicant: The Government of the United States of America, Department of Health and Human ServicesInventors: Robert C. Moschel, Anthony E. Pegg, M. Eileen Dolan, Mi-Young Chae
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Patent number: 6333331Abstract: The present invention provides AGT inactivating compounds such as substituted O6-benzylguanines of the formula 7- or 9-substituted 8-aza-O6-benzylguanines, 7,8-disubstituted O6-benzylguanines, 7,9-disubstituted O6-benzylguanines, 4(6)-substituted 2-amino-5-nitro-6(4)-benzyloxypyrimidines, and 4(6)-substituted 2-amino-5-nitroso-6(4)-benzyloxypyrimidines, as well as pharmaceutical compositions comprising such compounds along with a pharmaceutically acceptable carrier.Type: GrantFiled: June 15, 1999Date of Patent: December 25, 2001Assignees: The United States of America as represented by the Department of Health and Human Services, The Penn State Research Foundation, ARCH Development CorporationInventors: Robert C. Moschel, Anthony E. Pegg, M. Eileen Dolan, Mi-Young Chae
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Patent number: 6303604Abstract: The present invention provides 8-substituted O6-benzylguanine, 4(6)-substituted 2-amino-5-nitro-6(4)-benzyloxypyrimidine, and 4(6)-substituted 2-amino-5-nitroso-6(4)-benzyloxypyrimidine derivatives which have been found to be effective AGT inactivators, as well as pharmaceutical compositions comprising such derivatives along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O6-position of quanine, by administering to a mammal an effective amount of one of the aforesaid derivatives, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O6-benzylguanine, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O6-position of guanine.Type: GrantFiled: June 9, 2000Date of Patent: October 16, 2001Assignees: The United States of America as represented by the Department of Health and Human Services, The Penn State Research Foundation, Arch Development CorporationInventors: Robert C. Moschel, Anthony E. Pegg, M. Eileen Dolan, Mi-Young Chae
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Patent number: 6172070Abstract: The present invention provides 8-substituted O6-benzylguanine, 4(6)-substituted 2-amino-5-nitro-6(4)-benzyloxypyrimidine, and 4(6)-substituted 2-amino-5-nitroso-6(4)-benzyloxypyrimidine derivatives which have been found to be effective AGT inactivators, as well as pharmaceutical compositions comprising such derivatives along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O6-position of guanine, by administering to a mammal an effective amount of one of the aforesaid derivatives, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O6-benzylguanine, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O6-position of guanine.Type: GrantFiled: May 25, 1999Date of Patent: January 9, 2001Assignees: The United States of America as represented by the Department of Health and Human Services, The Penn State Research Foundation, Arch Development CorporationInventors: Robert C. Moschel, Anthony E. Pegg, M. Eileen Dolan, Mi-Young Chae
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Patent number: 6060458Abstract: The present invention provides a single-stranded oligodeoxyribonucleotide, which (i) comprises from about 5 to 11 bases, at least one of which is a substituted or an unsubstituted O.sup.6 -benzylguanine, and (ii) inactivates human AGT. The present invention also provides a single-stranded oligodeoxyribonucleotide, which can inactivate a mutant human AGT, which either is not inactivated by O.sup.6 -benzylguanine or is less inactivated by O.sup.6 -benzylguanine than by said single-stranded oligodeoxyribonucleotide. A phosphate of the single-stranded oligodeoxyribonucleotide can be replaced by a methylphosphonate or a phosphorothioate. The present invention also provides a composition comprising such an oligodeoxyribonucleotide. In addition, the present invention provides a method of enhancing the effect of an antineoplastic alkylating agent, which alkylates the O.sup.Type: GrantFiled: February 13, 1998Date of Patent: May 9, 2000Assignees: The United States of America as represented by the Department of Health and Human Services, The Penn State Research Foundation, Arch Development CorporationInventors: Robert C. Moschel, Gary T. Pauly, Anthony E. Pegg, M. Eileen Dolan
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Patent number: 5965126Abstract: The present invention relates to methods of treating neoplastic disease whereby gene therapy treatments are employed in combination with a chemotherapy regime. A combinational therapy with anti-neoplastic alkylating agents will optimize host tumor sensitivity to these agents used alone or in combination with O.sup.6 -benzylguanine (BG) or a similar compound or compounds. Hematopoietic cells are infected with a transgene expressing a mutant AGT protein exhibiting DNA repair activity while imparting resistance to BG or a related compound. Introduction of the transduced hematopoietic cell population expressing the mutant AGT protein into the patient in tandem with the chemotherapeutic regime will substantially reduce myelosuppression traditionally associated with the administration of these anti-neoplastic drugs.Type: GrantFiled: March 25, 1996Date of Patent: October 12, 1999Assignee: The Penn State Research FoundationInventors: Anthony E. Pegg, Stanton L. Gerson
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Patent number: 5958932Abstract: The present invention provides AGT inactivating compounds such as substituted O.sup.6 -benzylguanines of the formula ##STR1## wherein, for example, R.sub.1 is amino, hydroxy, or alkylamino, R.sub.2 is aminoalkyl, hydroxyalkyl, or alkylaminoalkyl, and R.sub.3 is halo, hydroxyalkyl, thiol or alkylthio, as well as pharmaceutical compositions comprising such compounds and a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine comprising administering to a mammal an effective amount of one of the aforesaid compounds and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine.Type: GrantFiled: April 28, 1997Date of Patent: September 28, 1999Assignees: The United States of America as represented by the Secretary of the Department of Health and Human Services, Arch Development Corporation, Penn State Research FoundationInventors: Robert C. Moschel, Anthony E. Pegg, M. Eileen Dolan, Mi-Young Chae
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Patent number: 5916894Abstract: The present invention provides 8-substituted O.sup.6 -benzylguanine derivatives which have been found to be effective AGT inactivators, as well as pharmaceutical compositions comprising such derivatives along with a pharmaceutically acceptable carrier. Thus, for example, the present invention provides a compound of the formula ##STR1## wherein R.sub.1 is a substituent selected from the group consisting of amino, hydroxy, C.sub.1 -C.sub.4 alkylamino, C.sub.1 -C.sub.4 dialkylamino, and C.sub.1 -C.sub.4 acylamino, R.sub.2 is a substituent selected from the group consisting of C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 dialkylamino alkyl, and C.sub.1 -C.sub.4 pivaloylalkyl, and R.sub.3 is a C.sub.1 -C.sub.4 alkyl. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lessons at the O.sup.Type: GrantFiled: September 11, 1997Date of Patent: June 29, 1999Assignees: The United States of America as represented by the Department of Health and Human Services, The Penn State Research Foundation, Arch Development CorporationInventors: Robert C. Moschel, Anthony E. Pegg, M. Eileen Dolan, Mi-Young Chae
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Patent number: 5753668Abstract: The present invention provides certain novel nitro or nitroso substituted benzyloxy pyrimidines useful as AGT inactivators. An example of such a pyrimidine is a compound of the formula ##STR1## wherein R.sub.1, is NO.sub.2 or NO, and R.sub.2 is hydrogen, halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 hydroxyalkyl, thiol, C.sub.1 -C.sub.4 alkythio, trifluoromethoxy, oxymethanesulfonyl, oxytrifluoromethanesulfonyl, or C.sub.1 -C.sub.4 oxyacyl. The present invention further provides pharmaceutical compositions comprising these compounds, and a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine.Type: GrantFiled: June 11, 1996Date of Patent: May 19, 1998Assignees: The United States of America as represented by the Department of Health and Human Services, Penn State Research Foundation, Arch Development CorporationInventors: Robert C. Moschel, Anthony E. Pegg, M. Eileen Dolan, Mi-Young Chae
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Patent number: 5691307Abstract: Novel O.sup.6 -substituted guanine compounds and pharmaceutical compositions thereof are useful for effectively reducing O.sup.6 -alkylguanine-DNA alkyltransferase (AGT). The novel compounds are useful for treating tumors and when used with anti-neoplastic alkylating agents enhance the chemotherapeutic treatment of tumor cells in a host.Type: GrantFiled: June 7, 1994Date of Patent: November 25, 1997Assignees: The United States of America as represented by the Department of Health and Human Services, The Penn State Research Foundation, Arch Development CorporationInventors: Robert C. Moschel, M. Eileen Dolan, Anthony E. Pegg, Mark G. McDougall, Mi-Young Chae
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Patent number: 5525606Abstract: The present invention provides 8-substituted O.sup.6 -benzylguanines of the formula ##STR1## wherein R.sub.1, R.sub.2, and R.sub.3 are as defined in the specification, and 4(6)-substituted 2-amino-5-nitro-6(4)-benzyloxypyrimidine, and 4(6)-substituted 2-amino-5-nitroso-6(4)-benzyloxypyrimidine derivatives which have been found to be effective AGT inactivators, as well as pharmaceutical compositions comprising such derivatives along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine, by administering to a mammal an effective amount of one of the aforesaid derivatives, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O.sup.Type: GrantFiled: August 1, 1994Date of Patent: June 11, 1996Assignees: The United States of America as represented by the Department of Health and Human Services, ARCH Development Corporation, Penn State Research Foundation, Inc.Inventors: Robert C. Moschel, Anthony E. Pegg, M. Eileen Dolan, Mi-Young Chae
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Patent number: 5358952Abstract: O.sup.6 -substituted guanine compounds of the formula ##STR1## wherein R is a benzyl group or a substituted benzyl group, cause a depletion of O.sup.6 -alkylguanine-DNA alkyltransferase (AGT) activity in mammalian cells. These compounds may be administered to a host so as to reduce AGT levels in tumor cells of the host in order to increase host responsiveness to anti-neoplastic alkylating agents, including chloroethylating agents, such as chloroethylnitrosoureas, for chemotherapeutic treatment of a number of neoplasms.Type: GrantFiled: December 12, 1991Date of Patent: October 25, 1994Assignees: The United States of America as represented by the Secretary of the Department of Health and Human Services, The Penn State Research FoundationInventors: Robert C. Moschel, M. Eileen Dolan, Anthony E. Pegg
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Patent number: 5352669Abstract: O.sup.6 -Benzylated guanine guanosine and 2'-deoxyguanosine compounds of the formula ##STR1## wherein Z is hydrogen, ##STR2## and R is a benzyl group or a substituted benzyl group, cause a depletion of O.sup.6 -alkylguanine-DNA alkyltransferase (AGT) activity in mammalian cells. These compounds may be administered to a host so as to reduce AGT levels in tumor cells of the host in order to increase host responsiveness to anti-neoplastic alkylating agents, including chloroethylating agents, such as chloroethylnitrosoureas, for chemotherapeutic treatment of a number of neoplasms.Type: GrantFiled: November 21, 1990Date of Patent: October 4, 1994Assignee: The of the United States of America as represented by the Department of Health and Human ServicesInventors: Robert C. Moschel, M. Eileen Dolan, Anthony E. Pegg
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Patent number: 5091430Abstract: O.sup.6 -substituted guanine compounds of the formula ##STR1## wherein R is a benzyl group or a substituted benzyl group, cause a depletion of O.sup.6 -alkylguanine-DNA alkyltransferase (AGT) activity in mammalian cells. These compounds may be administered to a host so as to reduce AGT levels in tumor cells of the host in order to increase host responsiveness to anti-neoplastic alkylating agents, including chloroethylating agents, such as chloroethylnitrosoureas, for chemotherapeutic treatment of a number of neoplasms.Type: GrantFiled: March 13, 1990Date of Patent: February 25, 1992Assignee: The United States of America as represented by the Secretary of the Department of Health and Human ServicesInventors: Robert C. Moschel, M. Eileen Dolan, Anthony E. Pegg