Cell death-inducing agent, cell growth-inhibiting agent, and pharmaceutical composition for treatment of disease caused by abnormal cell growth

Patent metadata

Field	Value
Publication number	US-2016202242-A1
Application number	US-201514980055-A
Country	US
Kind code	A1
Filing date	Dec 28, 2015
Priority date	Dec 26, 2014
Publication date	Jul 14, 2016
Grant date	—

Abstract

It is intended to induce cell death and inhibit cell growth for cancer cells.
The agents of the present invention comprise, as active ingredients, a drug inhibiting GST-π and a drug inhibiting a homeostasis-related protein that exhibits synthetic lethality when inhibited together with GST-π.

First claim

1 . A cell death-inducing agent for a cancer cell comprising, as active ingredients, a drug inhibiting GST-π and a drug inhibiting a homeostasis-related protein that exhibits synthetic lethality when inhibited together with GST-π.

2 . A cell growth-inhibiting agent for a cancer cell comprising, as active ingredients, a drug inhibiting GST-π and a drug inhibiting a homeostasis-related protein that exhibits synthetic lethality when inhibited together with GST-π.

3 . The agent according to claim 1 , wherein the homeostasis-related protein that exhibits synthetic lethality along with the inhibition of GST-π is a protein selected from the group consisting of a cell cycle-regulating protein, an anti-apoptosis-related protein, and a PI3K signaling pathway-related protein.

4 . The agent according to claim 3 , wherein the cell cycle-regulating protein that exhibits synthetic lethality along with the inhibition of GST-π is at least one cell cycle-regulating protein selected from the group consisting of ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH, BRSK1, MCM8, CCNB3, MCMDC1 and MYLK.

5 . The agent according to claim 3 , wherein the cell cycle-regulating protein that exhibits synthetic lethality along with the inhibition of GST-π is at least one protein selected from the group consisting of p21, RNPC1, CCNL1, MCM8, CCNB3, and MCMDC1.

6 . The agent according to claim 3 , wherein the anti-apoptosis-related protein that exhibits synthetic lethality along with the inhibition of GST-π is at least one anti-apoptosis-related protein selected from the group consisting of AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1, BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, and MYO18A.

7 . The agent according to claim 3 , wherein the PI3K signaling pathway-related protein that exhibits synthetic lethality along with the inhibition of GST-π is at least one PI3K signaling pathway-related protein selected from the group consisting of MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1, PIK3CA, and SRF.

8 . The agent according to claim 1 , wherein the drug is a substance selected from the group consisting of an RNAi molecule, a ribozyme, an antisense nucleic acid, a DNA/RNA chimeric polynucleotide, and a vector for expressing at least one of them.

9 . The agent according to claim 1 , wherein the drug inhibiting a homeostasis-related protein is a compound that acts on the homeostasis-related protein.

10 . The agent according to claim 1 , wherein the agent induces apoptosis.

11 . The agent according to claim 1 or 2 , wherein the cancer cell is a cancer cell highly expressing GST-π.

12 . A pharmaceutical composition for the treatment of a disease caused by abnormal cell growth, comprising an agent according to claim 1 .

13 . The pharmaceutical composition according to claim 12 , wherein the disease is a cancer.

14 . The pharmaceutical composition according to claim 13 , wherein the cancer is a cancer highly expressing GST-π.

15 . A method for screening for a cell death-inducing agent and/or a cell growth-inhibiting agent for a cancer cell that is used together with a drug inhibiting GST-π, comprising a step of selecting a drug inhibiting a homeostasis-related protein that exhibits synthetic lethality when inhibited together with GST-π.

16 . The screening method according to claim 15 , comprising the steps of: contacting a test substance with a cancer cell; measuring the expression level of the homeostasis-related protein in the cell; and selecting the test substance as a drug inhibiting the homeostasis-related protein when the expression level is decreased compared with that measured in the absence of the test substance.

17 . The screening method according to claim 15 , wherein the homeostasis-related protein that exhibits synthetic lethality along with the inhibition of GST-π is a protein selected from the group consisting of a cell cycle-regulating protein, an anti-apoptosis-related protein, and a PI3K signaling pathway-related protein.

18 . The screening method according to claim 17 , wherein the cell cycle-regulating protein that exhibits synthetic lethality along with the inhibition of GST-π is at least one cell cycle-regulating protein selected from the group consisting of ATM, CDC25A, p21, PRKDC, RBBP8, SKP2, MCM10, RNPC1, CCNL1, CENPH, BRSK1, MCM8, CCNB3, MCMDC1 and MYLK.

19 . The screening method according to claim 17 , wherein the cell cycle-regulating protein that exhibits synthetic lethality along with the inhibition of GST-π is at least one protein selected from the group consisting of p21, RNPC1, CCNL1, MCM8, CCNB3, and MCMDC1.

20 . The screening method according to claim 17 , wherein the anti-apoptosis-related protein that exhibits synthetic lethality along with the inhibition of GST-π is at least one anti-apoptosis-related protein selected from the group consisting of AATF, ALOX12, ANXA1, ANXA4, API5, ATF5, AVEN, AZU1, BAG1, BCL2L1, BFAR, CFLAR, IL2, MALT1, MCL1, MKL1, MPO, MTL5, MYBL2, and MYO18A.

21 . The screening method according to claim 16 , wherein the PI3K signaling pathway-related protein that exhibits synthetic lethality along with the inhibition of GST-π is at least one PI3K signaling pathway-related protein selected from the group consisting of MTOR, IRAK1, IRS1, MYD88, NFKB1, PIK3CG, RAC1, AKT3, EIF4B, EIF4E, ILK, MTCP1, PIK3CA, and SRF.

Assignees

• Nitto Denko Corp

Inventors

• Tanaka Hiroyuki
• Minomi Kenjirou
• Niitsu Yoshiro

Classifications

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• G01N33/5011 Primary

  for testing antineoplastic activity · CPC title