Abstract: The subject invention concerns materials and methods for inhibiting the Akt/PKB pathway. In one embodiment, a compound of the invention inhibits kinase activity and/or phosphorylation levels of Akt proteins. The subject invention also concerns methods for inhibiting or killing a cancer cell or other cell in which expression of an Akt protein is elevated or constitutively active, comprising contacting the cell with an effective amount of a compound of formula I. The subject invention also concerns methods for treating cancer or a tumor in a person or animal comprising administering all effective amount of a compound of formula I to the person or animal.

Abstract: Growth factor binding compounds having a plurality of acyclic isophthalic acid groups attached to a non-peptide organic scaffold and pharmaceutical compositions of the same are disclosed. Methods of administering and using the growth factor binding compounds or the growth factor binding compositions are also taught. These novel growth factor binding compounds are useful for treating angiogenesis, excessive cellular proliferation, tumor growth, and a combination thereof as well as inhibiting growth factor binding to cells and phosphorylation.

Abstract: The subject invention pertains to a transgenic animal model for tumorigenesis having a genome comprising a ras transgene and which is heterozygous or homozygous for a null p27 gene, and methods of using such animal to screen compounds or evaluate treatments for oncogenic and antitumor activity. The subject invention further concerns a transgenic mouse comprising a ras transgene and which has a genome that is wild-type p27+/+, and wherein the mouse has an FVB/N and C57BL/6X 129 genetic background; and methods of using such transgenic mice to screen compounds or evaluate treatments for oncogenic or antitumor activity. Advantageously, the female animals of the subject invention are fertile and capable of nursing their young. The subject invention also pertains to in vitro systems including isolated cells or tissues of animal models for tumorigenesis, which can be used to screen compounds and treatments for oncogenic and antitumor activity.

Abstract: Compounds and associated methods for inhibiting a protein tyrosine phosphatase. By a combination of experimental and virtual screenings of the NCI Diversity Set chemical library, NSC-87877 and NSC-117199 have been identified as Shp2 PTP inhibitors. Significantly, NSC-87877 is active in cell-based assays and has no detectable off-target effects in the EGF-stimulated Erk1/2 activation pathway. Additionally, a number of analogs of NSC-117199 have been produced. These analogs exhibit enhanced protein tyrosine phosphatase inhibition and are found to be potent and/or selective inhibitors of Shp1 and/or Shp2 protein tyrosine phosphatases.

Abstract: Most human tumors find ways to resist anticancer drug monotherapy. Akt is considered a likely peptide providing such monotherapy drug resistance. Data indicates that Akt chemoresistance is induced in a p53-dependent manner and that inhibition of Akt may be an effective means of overcoming chemoresistance in cancer cells expressing wild-type p53. Breast, ovarian, lung cancer and leukemia cells lines were treated with combinations of Akt activation inhibitor Triciribine (TCN) or Triciribine phosphate (TCNP) and chemotherapeutic drugs to determine the efficiency of combination therapy. Additionally, cells were introduced into xenograft models to determine in vivo effects of combination treatment. Combining TCN or TCNP with other anticancer drugs overcame cytotoxic or treatment resistance. Thus, TCN and TCNP are shown to broaden the spectrum of human tumors that can be effectively treated.

Abstract: The subject invention concerns compositions and methods for blocking cancer cell growth or proliferation and/or inducing cancer cell death. Compositions of the present invention are peptidomimetics that inhibit STAT function. Peptidomimetics of the invention include compounds of the formula RY*L (where Y* represents phosphotyrosine), with the R group at the Y-1 position. Peptidomimetics of the invention disrupt Stat3 activation and function. Peptidomimetics of the invention significantly inhibit tumor cell growth and induce tumor cell death.

Abstract: The protein RhoB and its variants as a supressor of cancer cell growth, inhibitor of malignant cell transformation, and modulator of oncogenic signaling, wherein introducing RhoB directly, or indirectly via a nucleic acid, into a malignantly transformed cell or a cancerous cell decreases phosphorylation of Erk and Akt proteins inhibiting the PI3-kinase/Akt cell survival pathway and promoting apoptotic cell death. Methods and compositions are disclosed for administering to cancer patients, a prophylactic treatment to minimize the risk of malignant transformation, and advantageous combination of RhoB therapy with existing cancer treatments. The protein RhoB and the variants of the present invention are prenylated with either geranylgeranyl or farnesyl, and provision is made for selection of the prenylating moiety.

Abstract: The present invention concerns the use of the protein RhoB and its variants to inhibit cancer cell growth, migration, invasion, metastasis, malignant cell transformation, and/or to modulate oncogenic signaling, wherein introducing RhoB directly, or indirectly via a nucleic acid sequence encoding RhoB, into a malignantly transformed cell or a cancerous cell decreases phosphorylation of Erk and Akt proteins inhibiting the PI3-kinase/Akt cell survival pathway and promoting apoptotic cell death. In one aspect, the compositions and methods of the present invention are used to inhibit the malignant transformation of cells by the oncogenes H-Ras, N-Ras, K-Ras, EGFR, or ErbB2, or to inhibit the growth of cancer cells transformed by such oncogenes. The compositions and methods of the present invention may be used to inhibit cancer cell growth, inhibit malignant cell transformation, and modulate oncogenic signaling in vivo or in vitro.

Abstract: The present invention concerns the use of the protein RhoB and its variants to inhibit cancer cell growth, migration, invasion, metastasis, malignant cell transformation, and/or to modulate oncogenic signaling, wherein introducing RhoB directly, or indirectly via a nucleic acid sequence encoding RhoB, into a malignantly transformed cell or a cancerous cell decreases phosphorylation of Erk and Akt proteins inhibiting the PI3-kinase/Akt cell survival pathway and promoting apoptotic cell death. In one aspect, the compositions and methods of the present invention are used to inhibit the malignant transformation of cells by the oncogenes H-Ras, N-Ras, K-Ras, EGFR, or ErbB2, or to inhibit the growth of cancer cells transformed by such oncogenes. The compositions and methods of the present invention may be used to inhibit cancer cell growth, inhibit malignant cell transformation, and modulate oncogenic signaling in vivo or in vitro.

Abstract: The subject invention pertains to a transgenic animal model for tumorigenesis having a genome comprising a ras transgene and which is heterozygous or homozygous for a null p27 gene, and methods of using such animal to screen compounds or evaluate treatments for oncogenic and antitumor activity. The subject invention further concerns a transgenic mouse comprising a ras transgene and which has a genome that is wild-type p27+/+, and wherein the mouse has an FVB/N and C57BLU6 X 129 genetic background; and methods of using such transgenic mice to screen compounds or evaluate treatments for oncogenic or antitumor activity. Advantageously, the female animals of the subject invention are fertile and capable of nursing their young. The subject invention also pertains to in vitro systems including isolated cells or tissues of animal models for tumorigenesis, which can be used to screen compounds and treatments for oncogenic and antitumor activity.

Abstract: The subject invention pertains to the treatment of tumors and cancerous tissues and the prevention of tumorigenesis and malignant transformation through the modulation of JAK/STAT3 intracellular signaling. The subject invention concerns pharmaceutical compositions containing cucurbitacin I, or a pharmaceutically acceptable salt or analog thereof, to a patient, wherein the tumor is characterized by the constitutive activation of the JAK/STAT3 intracellular signaling pathway. The present invention further pertains to methods of moderating the JAK and/or STAT3 signaling pathwaysin vitro or in vivo using cucurbitacin I, or a pharmaceutically acceptable salt or analog therof. Another aspect of the present invention concerns a method for screening candidate compoudns for JAK AND/or STAT3 inhibition and anti-tumor activity.

Abstract: Compounds having the formula or a pharmaceutically acceptable salt thereof wherein R1 is (a) hydrogen, (b) loweralkyl, (c) alkenyl, (d) alkoxy, (e) thioalkoxy, (f) halo, (g) haloalkyl, (h) aryl-L2—, and (i) heterocyclic-L2—; R2 is selected from (e) —C(O)NH—CH(R14)-tetrazolyl, (f) —C(O)NH-heterocyclic, and (g) —C(O)NH—CH(R14)—C(O)NR17R18; R3 is heterocyclic, aryl, substituted or unsubstituted cycloalkyl; R4 is hydrogen, lower alkyl, haloalkyl, halogen, aryl, arylakyl, heterocyclic, or (heterocyclic)alkyl; L1 is absent or is selected from (a) —L4—N(R5)—L5—, (b) —L4—O—L5—, (c) —L4—S(O)n—L5— (d) —L4—L6—C(W)—N(R5)—L5—, (e) —L4—L6—S(O)m—N(R5)—L5—, (f) —L4—N(R5)—C(W)—L7—L5—, (g) —L4—N(R5)—S(O)p—L7—L5—, (h) optionally subs

Abstract: A transgenic rodent that constitutively expresses a ras protein in at least one tissue, is p21 null in at least one chromosome, and exhibits enhanced and accelerated ras-dependent tumorigenesis, together with methods for using said rodent, or cells derived thereof, for screening compounds or treatments for antitumor activity. In preferred embodiments, the rodent is a transgenic mouse that expresses a human ras oncogene operably linked to human regulatory sequences, and the cells of the mouse have at least one copy of a p21WAF1/ClP1transgene, whereby the mouse constitutively expresses a ras oncogene, and has decreased expression of p21. The rodents of the invention are useful in the study of ras-dependent oncogenesis and in the developments of treatments thereto.

Abstract: The protein RhoB and its variants as a supressor of cancer cell growth, inhibitor of malignant cell transformation, and modulator of oncogenic signaling, wherein introducing RhoB directly, or indirectly via a nucleic acid, into a malignantly transformed cell or a cancerous cell decreases phosphorylation of Erk and Akt proteins inhibiting the PI3-kinase/Akt cell survival pathway and promoting apoptotic cell death. Methods and compositions are disclosed for administering to cancer patients, a prophylactic treatment to minimize the risk of malignant transformation, and advantageous combination of RhoB therapy with existing cancer treatments. The protein RhoB and the variants of the present invention are prenylated with either geranylgeranyl or farnesyl, and provision is made for selection of the prenylating moiety.

Abstract: Compounds having the formula 1

Abstract: The invention relates to a method of conferring radiation sensitivity on a tumor cell comprising administering to the cell an inhibitor of a protein product which participates in the ras signalling pathway, whereby inhibition of the protein product confers radiation sensitivity on the cell.

Abstract: Compounds having the formula or a pharmaceutically acceptable salt thereof wherein R1 is (a) hydrogen, (b) loweralkyl, (c) alkenyl, (d) alkoxy, (e) thioalkoxy, (f) halo, (g) haloalkyl, (h) aryl-L2—, and (i) heterocyclic-L2—; R2 is selected from (a) (b) —C(O)NH—CH(R14)—C(O)OR15, (d) —C(O)NH—CH(R14)—C(O)NHSO2R16, (e) —C(O)NH—CH(R14)-tetrazolyl, (f) —C(O)NH-heterocyclic, and (g) —C(O)NH—CH(R14)—C(O)NR17R18; R3 is substituted or unsubstituted heterocyclic or aryl, substituted or unsubstituted cycloalkyl or cycloalkenyl, and —P(W)RR3RR3′; R4 is hydrogen, lower alkyl, haloalkyl, halogen, aryl, arylakyl, heterocyclic, or (heterocyclic)alkyl; L1 is absent or is selected from (a) —L4—N(R5)—L5—, (b) —L4—O—L5—, (c) —L4—S(O)n—L5— (d) —L4—L6—C(W)—N(R5)—L5&

Abstract: Compounds having the formula or a pharmaceutically acceptable salt thereof wherein R1 is (a) hydrogen, (b) loweralkyl, (c) alkenyl, (d) alkoxy, (e) thioalkoxy, (f) halo, (g) haloalkyl, (h) aryl-L2—, and (i) heterocyclic-L2—; R2 is selected from (a) (b) —C(O)NH—CH(R14)—C(O)OR15, (d) —C(O)NH—CH(R14)—C(O)NHSO2R16, (e) —C(O)NH—CH(R14)-tetrazolyl, (f) —C(O)NH-heterocyclic, and (g) —C(O)NH—CH(R14)—C(O)NR17R18; R3 is substituted or unsubstituted heterocyclic or aryl, substituted or unsubstituted cycloalkyl or cycloalkenyl,  and —P(W)RR3RR3′; R4 is hydrogen, lower alkyl, haloalkyl, halogen, aryl, arylakyl, heterocyclic, or (heterocyclic)alkyl; L1 is absent or is selected from (a) —L4—N(R5)—L5—, (b) —L4—O—L5—, (c) —L4—S(O)n—L5—(d) —L4—L6—C(W)—N(R5)&md

Abstract: Compounds having the formula or a pharmaceutically acceptable salt thereof wherein R1 is (a) hydrogen, (b) loweralkyl, (c) alkenyl, (d) alkoxy, (e) thioalkoxy, (f) halo, (g) haloalkyl, (h) aryl-L2—, and (i) heterocyclic-L2—; R2 is selected from (b) —C(O)NH—CH(R14)—C(O)OR15, (d) —C(O)NH—CH(R14)—C(O)NHSO2R16, (e) —C(O)NH—CH(R14)-tetrazolyl, (f) —C(O)NH-heterocyclic, and (g) —C(O)NH—CH(R14)—C(O)NR17R18; R3 is heterocyclic, aryl, substituted or unsubstituted cycloalkyl; R4 is hydrogen, lower alkyl, haloalkyl, halogen, aryl, arylakyl, heterocyclic, or (heterocyclic)alkyl; L1 is absent or is selected from (a) —L4—N(R5)—L5—, (b) —L4—O—L5—, (c) —L4—S(O)n—L5— (d) —L4—L6—C(W)—N(R5)—L5—, (e) —L4—L6—S(O)m—N(R5)—L5 —, (f) —L4—N(R5)&m

Abstract: Method of blocking aberrant Ras signaling in a mammal while avoiding excessive cell toxicity by administration of lovastatin and geranylgeraniol.