WO2008004130A2 - Peptides for targeting the mitochondrial transition pore complex for therapeutic apoptosis induction and biological applications - Google Patents
Peptides for targeting the mitochondrial transition pore complex for therapeutic apoptosis induction and biological applications Download PDFInfo
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- WO2008004130A2 WO2008004130A2 PCT/IB2007/002940 IB2007002940W WO2008004130A2 WO 2008004130 A2 WO2008004130 A2 WO 2008004130A2 IB 2007002940 W IB2007002940 W IB 2007002940W WO 2008004130 A2 WO2008004130 A2 WO 2008004130A2
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- csnrdarrc
- indicates
- disulfide bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
Definitions
- the invention relates to peptides for targeting the Mitochondrial Membrane Permeabilization (MMP) for Therapeutic Apoptosis Induction. It also relates to the biological applications thereof, particularly to pharmaceutical compositions for treating diseases associated with apoptosis, especially cancers.
- MMP Mitochondrial Membrane Permeabilization
- the permeability transition pore (PTP) , a polyprotein complex, participates in the mitochondrial homeostasis as well as in the mitochondrial phase of the intrinsic pathway of apoptosis. It integrates multiple death signals including alterations of the intracellular milieu, translocation of pro-apoptotic members of the Bax/Bcl-2 family, p53, and viral pro-teins. As a consequence, PTP can act as a coordinator of the pro- apoptotic mitochondrial membrane permeabilization process and the release of pro-apoptotic intermembrane space proteins into the cytosol. Moreover, the deregulation of PTP has been involved in several major human pathologies such as cancer, neurodegeneration, ischemia/reperfusion, aging, as well as hepatotoxicity.
- Herpes virus HBx from Hepatitis B, PB1-F2 protein from influ- enza virus ; BH3 peptides and MIlL from Myxoma virus.
- the invention relates to a method for treating pathologies or pathological events in which PTP is implicated.
- the peptides having an apoptogen peptidic domain via the mitochondria have an amido group at C-terminal end, or correspond to the D derivatives or retroinverso derivatives.
- Preferred peptides are selected in the following group of peptides having sequences SEQ ID N°33 to 37:
- said peptides have, respectively, an atnido group at the C-terminal end an amido group at C-terminal and a biotinyl group at the N- terminal end - an atnido group at C-terminal and a biotinyl group at the N- terminal end an amido group at C-terminal and a biotinyl group at the N- terminal end
- said peptides can have the following modifications : - an amido group at the C-terminal end
- the above disclosed peptides are compounds of high interest to treat diseases associated with insufficient apoptosis or programmed cell death. Particularly they are antitumoral derivatives of high value, especially for treating solid tumors, such as bladder cancers in humans.
- the above disclosed peptides are compounds of high interest to treat cancers .
- they are antitumoral derivatives of high value, especially for treating solid tumors, particularly bladder cancers in humans .
- the invention also relates to pharmaceutical compositions comprising a therapeutically ef fective amount of at least one peptide such as above def ined an association with a pharmaceutically acceptable carrier .
- compositions are administered topically or by injection and comprise the above defined active principles at doses chosen by the one skilled in the art depending on the disease to be treated, the state and age of the patient.
- compositions of the invention are particularly useful for treating cancers, especially solid tumors .
- the invention also relates to a method of treatment of solid cancers comprising administering to a protein in need thereof a therapeutically efficient amount of at least one peptide such as above defined.
- Figure 2A gives results concerning the reduction of the prostate tumoral growth by DTat [49-57] -GGLLFIHFRIGSRHSRIG and DTat [49-57] -GGRIAIWILRH-CONH2 and Figure 2B, the improvement of the survival ;
- Figure 3A gives results concerning the reduction of the bladder tumoral growth by rkkrrqrrr-GG-LLFIHFRIGSRHSRIG and Figure and 3B, the improvement of the survival.
- the relative tumor volumes (+/- SEM) are given for each condition;
- HTB-9 (bladder carcinoma) model is responsive to SEQ ID N°34 rkkrrqrrr-GG-LLFIHFRIGSRHSRIG at the dose 10 mg/kg, injected intratumoraly 3 times a week for 3 weeks.
- An antitumoral effect was observed with SEQ ID N°34 rkkrrqrrr-GG- LLFIHFRIGSRHSRIG as well as a significantly longer survival of bladder tumor bearing mice treated with the compound.
Abstract
The invention relates to peptides having an apoptogenic peptidic domain selected in the group comprising peptides having the sequences SEQ ID N°l-32. Said peptides are useful as drugs, particularly for treating solid cancers.
Description
Peptides for targeting the Mitochondrial Membrane Permeabilization for Therapeutic Cell Death Induction and biological applications
The invention relates to peptides for targeting the Mitochondrial Membrane Permeabilization (MMP) for Therapeutic Apoptosis Induction. It also relates to the biological applications thereof, particularly to pharmaceutical compositions for treating diseases associated with apoptosis, especially cancers.
The permeability transition pore (PTP) , a polyprotein complex, participates in the mitochondrial homeostasis as well as in the mitochondrial phase of the intrinsic pathway of apoptosis. It integrates multiple death signals including alterations of the intracellular milieu, translocation of pro-apoptotic members of the Bax/Bcl-2 family, p53, and viral pro-teins. As a consequence, PTP can act as a coordinator of the pro- apoptotic mitochondrial membrane permeabilization process and the release of pro-apoptotic intermembrane space proteins into the cytosol. Moreover, the deregulation of PTP has been involved in several major human pathologies such as cancer, neurodegeneration, ischemia/reperfusion, aging, as well as hepatotoxicity.
According to previous works, the inventors have proposed to use PTP as a pharmaceutical target .
This was validated in vitro and in vivo. It was shown that an HIV protease inhibitor, Nelfinavir, affects the pore function of ANT, a member of PTP, and prevents three acute pathologies in mouse via an inhibition of the apoptotic cell death J.Clin. Invest .2005 Weaver et al. Moreover, proteins and pep-
tides represent also a broad class of molecules acting on PTP. Some of them can promote directly PTP opening, whereas others can maintain the pore in a closed state, preventing its
2+ opening by other compounds such as Ca , Atr, pro-oxidants or even other peptides. Endogenous, viral, or bacterial
(e.g. porB) proteins have been shown to modulate the activity of various members of PTP. This applies to Bax/Bcl-2 family members (Bax, Bcl-2, BcI-XL, Bid) ; Vpr from HIV-I, vMIA from
Herpes virus, HBx from Hepatitis B, PB1-F2 protein from influ- enza virus ; BH3 peptides and MIlL from Myxoma virus.
The previous characterization of molecular mechanisms of these natural proteins led the inventors to design modified peptides with novel properties in an innovative therapeutic perspective.
It is then an object of the invention to provide new peptides to modulate apoptosis and/or cell death.
It is another object to provide drugs containing said peptides as active principles .
According to still another object, the invention relates to a method for treating pathologies or pathological events in which PTP is implicated.
The invention thus relates to peptides selected in the group comprising an apoptogenic peptidic domain via the mitochondria and/or a cellular penetration or recognition domain.
Preferred peptides having an apoptogenic peptidic domain are selected in the group comprising peptides having the following sequences SEQ ID N°l-22:
SEQ ID N°l: LLFIHFRIGSRHSRIG
SEQ ID N°2: LLFIHFRIGSRHSRI SEQ ID N°3: LLFIHFRIGSRHSR
SEQ ID N°4 : LLFIHFRIGSRHS
SEQ ID N05: RIAIWILRH
SEQ ID N°6: RWAIWILRH
SEQ ID N07: RIKIWILRH SEQ ID N°8: RISIWILRH
SEQ ID N09: RYAIWILRH
SEQ ID N°10: RIQIWILRH
SEQ ID N0Il: RITIWILRH
SEQ ID N°12: RILIWILRH SEQ ID N013: RFAIWILRH
SEQ ID N°14: RLAIWILRH
SEQ ID N°15: RIHIWILRH
SEQ ID N°16: KIAIWILRH
SEQ ID N°17: RIRIWILRH
SEQ ID N°18: LRVWRLCTRRL
SEQ ID N°19: LRVWRLSTRRL
SEQ ID N°20: LKTRVLKRWRL
SEQ ID N°21: ALFVHLRAGSNRSRIS
SEQ ID N°22: AVFIHFKRGSTSLGGG
Those peptides are advantageously fused or linked at the N Terminal end to cell penetration peptidic or non peptidic molecules preferentially selected in the group:
SEQ ID N°23: RKKRRQRRR
SEQ ID N°24: RRRRRRRRR
SEQ ID N°25: KKKKKKKKK
SEQ ID N°26: RRRQRRKKR
SEQ ID N°27: YARAAAARQARAGG
decanoyl-GG
decanoyl
12 , amino, 4,7, 10-trioxadodecanoyl-GG
12 , amino,4,7,10 -1rioxadodecanoy1
SEQ ID N°28: CSNRDARRC-GG
SEQ ID N°29: *CSNRDARRC* where "*" indicates intrachain disulfide bond between cysteine residues
SEQ ID N°30: *CSNRDARRC* -GG where "*" indicates intrachain disulfide bond between cysteine residues
SEQ ID N°31: GG-*CSNRDARRC*-GG- where "*" indicates intrachain disulfide bond between cysteine residues
SEQ ID N°32: GG-*CSNRDARRC* where "*" indicates intrachain disulfide bond between cysteine residues
Optionally, the peptides having an apoptogen peptidic domain via the mitochondria have an amido group at C-terminal end, or correspond to the D derivatives or retroinverso derivatives.
The peptides having the cellular penetration domain have optionally an acetyl group at the N-terminal end, a biotinyl group at the N-terminal and a glycin group at the C-terminal end, 2 glycins at the C-terminal end, 3 glycin groups at the C-terminal end, or correspond to the D derivatives or retroinverso derivatives.
Preferred peptides are selected in the following group of peptides having sequences SEQ ID N°33 to 37:
- SEQ ID N°33: D [RKKRRQRRR] -GG-LLFIHFRIGSRHSRIG
- SEQ ID N°34: RKKRRQRRR-GG-LLFIHFRIGSRHSRIG
- SEQ ID N°35: RKKRRQRRR-GG-D [LLFIHFRIGSRHSRIG]
- SEQ ID N°36: D[RKKRRQRRR]-GG-D[LLFIHFRIGSRHSRIG] - SEQ ID N°37: YARAAAARQARA-GG-LLFIHFRIGSRHSRIG
Particularly, said peptides have, respectively, an atnido group at the C-terminal end an amido group at C-terminal and a biotinyl group at the N- terminal end - an atnido group at C-terminal and a biotinyl group at the N- terminal end an amido group at C-terminal and a biotinyl group at the N- terminal end
Other preferred peptides have sequences SEQ ID N°38 to 43:
- SEQ ID N°38 D [RKKRRQRRR] -GG-RIAIWILRH
- SEQ ID N°39 D [RKKRRQRRR] -GG-RWAIWILRH
- SEQ ID N°40 RKKRRQRRR-GG-RIAIWILRH
- SEQ ID N°41 RKKRRQRRR-GG-D [RIAIWILRH] - SEQ ID N°42 D [RKKRRQRRR] -GG-D [RIAIWILRH]
- SEQ ID N°43 YARAAAARQARA-GG-RIAIWILRH
It will be noted that in the description and the claims, the designation Dtpeptidic sequence] means that the peptide is D isomer. The same meaning applies to a sequence with small letters .
Particularly, said peptides can have the following modifications : - an amido group at the C-terminal end
- an amido group at C-terminal and a biotinyl (or acetyl) group at the N-terminal end
- an amido group at C-terminal and an acetyl group at the N- terminal end
The above disclosed peptides are compounds of high interest to treat diseases associated with insufficient apoptosis or programmed cell death. Particularly they are antitumoral
derivatives of high value, especially for treating solid tumors, such as bladder cancers in humans.
Other preferred peptides include peptides having sequences SEQ ID N°44 to 51:
SEQ ID N°44: CSNRDARRC-GG-LLFIHFRIGSRHSRIG SEQ ID N°45: CSNRDARRC-GG-RIAIWILRH SEQ ID N°46: CSNRDARRC-LLFIHFRIGSRHSRIG SEQ ID N°47: CSNRDARRC-RIAIWILRH
SEQ ID N°48: *CSNRDARRC* -LLFIHFRIGSRHSRIG
SEQ ID N°49: *CSNRDARRC*-RIAIWILRH
SEQ ID N°50: GG- *CSNRDARRC*-GG-LLFIHFRIGSRHSRIG
SEQ ID N051: GG-*CSNRDARRC*-GG-RIAIWILRH
The above disclosed peptides are compounds of high interest to treat cancers . Particularly they are antitumoral derivatives of high value, especially for treating solid tumors, particularly bladder cancers in humans .
The invention also relates to pharmaceutical compositions comprising a therapeutically ef fective amount of at least one peptide such as above def ined an association with a pharmaceutically acceptable carrier .
These compositions are administered topically or by injection and comprise the above defined active principles at doses chosen by the one skilled in the art depending on the disease to be treated, the state and age of the patient.
The pharmaceutical compositions of the invention are particularly useful for treating cancers, especially solid tumors .
The invention also relates to a method of treatment of solid cancers comprising administering to a protein in need thereof a therapeutically efficient amount of at least one peptide such as above defined.
Other characteristics and advantages of the invention will be given hereinafter to illustrate the invention. It will be referred to Figures 1 to 3 , wherein
- Figures IA to ID give results concerning the antitumoral activity of DTat [49-57] -GGRIAIWILRH-CONH2 after injection to nude mice xenographted with PC-3 tumors,-
Figure 2A gives results concerning the reduction of the prostate tumoral growth by DTat [49-57] -GGLLFIHFRIGSRHSRIG and DTat [49-57] -GGRIAIWILRH-CONH2 and Figure 2B, the improvement of the survival ;
Figure 3A gives results concerning the reduction of the bladder tumoral growth by rkkrrqrrr-GG-LLFIHFRIGSRHSRIG and Figure and 3B, the improvement of the survival.
To illustrate the invention, in vivo experimental results are given hereinafter (nude mice, xenografted with PC3 human tumors) .
The experiments have been carried out with the 2 following peptides having sequences SEQ ID N°33 and 38:
SEQ ID N°33: D [RKKRRQRRR] -GG-LLFIHFRIGSRHSRIG SEQ ID N°38: D [RKKRRQRRR] -GG-RIAIWILRH
- Antitumoral activity of DTat [49-57] -GGRIAIWILRH-CONH2 after injection to nude mice xenographted with PC-3 tumors.
The results are given on figures IA-ID:
A - The tumors treated with DTat [49-57] -GGRIAIWILRH-CONH2were smaller than the controls treated with a carrier (NaCl 9%; CtR.). This is illustrated by the differences of volumes of the tumors between day 1 [O] and day 24 [•] . The means values are indicated by an horizontal line.
B - Concerns the following of the animal survival according to Kaplan-Meyer representation [Log rank test; n=9 animals/groups, p<0.05] .
C - Gives the volumes of the sub-cutaneos xenografted PC3 tumor measured before and after intra-tumoral administration of DTat [49-57] -GG-CONH2 (10 mg/Kg, n=8) [A] or RIAIWILRH-CONH2 (10 mg/Kg, n=8) [*] or DTat [49-57] -GGRIAIWILRH-CONH2 (10 mg/Kg, n=8) [■] or the carrier [NaCl 9%, •, n=8] 3 times/week during 3 weeks (starting from day 0) . The means of the tumor volumes (+/- SEM) for each condition are given on figure 1.
D - Distribution of the volumes of the tumors in treated mice (as in C) between day 1 [O] and day 50 [•] after the first injection. The mean values are indicated by an horizontal line.
- Reduction of the tumoral growth by DTat [49-57]- GGLLFIHFRIGSRHSRIG and DTat [49-57] -GGRIAIWILRH-CONH2 and improvement of the survival
Nude mice bearing PC3 prostatic human tumors were injected [i.t.] with DTat [49-57] -GGLLFIHFRIGSRHSRIG (Peptl)or DTat[49-
57] -GGRIAIWILRH-CONH2 (Pept2)(10 mg/kg per inj thrice a week, 3 weeks) . The results are given on figure 2. A: Evaluation of the mean volume of the tumors in mm3 (each point is the mean of 10 values +/- SD) . B: survival curves according to the 2 Kaplan-Meyer representation.
DTat [49-57] -GGLLFIHFRIGSRHSRIG or DTat [49-57] -GGRIAIWILRH-CONH2 derivatives having properties of high interest in the
MitoTrust® and their cytotoxic effect (MTT tests)
A. MitoTrust® test
SD = Standard deviation
B. MTT tests
Cancer cell lines
- Additional data on Cytotoxicity of SEQ ID N°34 rkkrrqrrr-GG- LLFIHFRIGSRHSRIG (cell viability in MTT assay)
(n=3)
SEQ ID N°33: rkkrrqrrr-GG-LLFIHFRIGSRHSRIG optimization
Sequences:
SEQ ID N°52 RRRQRRKKR -GG-LLFIHFRIGSRHSRIG
SEQ ID N°53 RRRRRRRRR-GG-LLFIHFRIGSRHSRIG
SEQ ID N°54 KKKKKKKKK-GG-LLFIHFRIGSRHSRIG
SEQ ID N°55 RRRQRRKKR-GG-LLFIHFRIGSRHSRIG
SEQ ID N°56 RRRQRRKKR-GG-LLFIHFRIGSRHS
SEQ ID N°57 DtRRRQRRKKR] -GG-LLFIHFRIGSRHSRIG
SEQ ID N°58 YARAAARQARA-GG-LLFIHFRIGSRHSRIG
SEQ ID N°59 LLFIHFRIGSRHSRIG-GG-rkkrrqrrr
Data :
Isolated mitochondria MTT assays
- In vivo ef ficiency of SEQ ID N°34 rkkrrqrrr-GG- LLFIHFRIGSRHSRIG on bladder tumors
Antitumor activity of SEQ ID N°34: rkkrrqrrr-GG- LLFIHFRIGSRHSRIG (i.t) given as single agent on human HTB-9 (bladder) tumor xenograft
The results are given on figures IA and IB:
Figure IA: Gives the volumes of the sub-cutaneous xenografted HTB-9 tumor measured before and after intra-tumoral administration of DTat [49-57] -GG-CONH2 (10 mg/Kg, n=9) [0] or the carrier (NaCl 9%, n=9) [♦] 3 times/week during 3 weeks
(starting from day 0) . The relative tumor volumes (+/- SEM) are given for each condition; Figure IB: concerns the following of the animal survival according to Kaplan-Meyer representation [Log rank test; n=9 animals/groups, p<0.05].
Conclusion: HTB-9 (bladder carcinoma) model is responsive to SEQ ID N°34 rkkrrqrrr-GG-LLFIHFRIGSRHSRIG at the dose 10 mg/kg, injected intratumoraly 3 times a week for 3 weeks. An antitumoral effect was observed with SEQ ID N°34 rkkrrqrrr-GG- LLFIHFRIGSRHSRIG as well as a significantly longer survival of bladder tumor bearing mice treated with the compound.
- Cytotoxicity of SEQ ID N°40 rkkrrqrrr-GG-RIAIWILRH (cell viability in MTT assay)
- Variant: SEQ ID N°39 RKKRRQRRR-GG-RWAIWILRH
cell viability in MTT assay:
Evaluations on mitochondria isolated from mice liver
MTT assays -
Other variant :
SEQ ID N°66 RIAIWILRH-GG-rkkrrqrrr
Isolated mitohondria MTT assays
Other mitochondrio-toxic sequences evaluation on isolated mitochondria
Claims
1. Peptides having an apoptogenic peptidic domain are selected in the group comprising peptides having the following sequences SEQ ID N°l-22:
SEQ ID N°l: LLFIHFRIGΞRHSRIG
SEQ ID N°2: LLFIHFRIGSRHSRI
SEQ ID N°3: LLFIHFRIGSRHSR
SEQ ID N°4: LLFIHFRIGSRHS
SEQ ID N05: RIAIWILRH
SEQ ID N° 6 : RWAIWILRH
SEQ ID N°7: RIKIWILRH
SEQ ID N08: RISIWILRH
SEQ ID N° 9 : RYAIWILRH
SEQ ID N°10: RIQIWILRH
SEQ ID N0Il: RITIWILRH
SEQ ID N°12: RILIWILRH
SEQ ID N°13: RFAIWILRH SEQ ID N°14: RLAIWILRH
SEQ ID N°15: RIHIWILRH
SEQ ID N°16: KIAIWILRH
SEQ ID N°17: RIRIWILRH
SEQ ID N°18: LRVWRLCTRRL
SEQ ID N019: LRVWRLSTRRL
SEQ ID N°20: LKTRVLKRWRL
SEQ ID N°21: ALFVHLRAGSNRSRIS
SEQ ID N°22: AVFIHFKRGSTSLGGG
and peptides fused or linked at the N Terminal end to cell penetration peptidic or non peptidic molecules selected in the group :
SEQ ID N023: RKKRRQRRR
SEQ ID N°24: RRRRRRRRR
SEQ ID N°25: KKKKKKKKK
SEQ ID N026: RRRQRRKKR
SEQ ID N027: YARAAAARQARAGG
decanoyl-GG decanoyl
12 , amino , 4 , 7 , 10 - trioxadodecanoyl -GG 12 , amino , 4 , 7 , 10 -trioxadodecanoyl SEQ ID N° 28 : CSNRDARRC-GG
SEQ ID N°29: *CSNRDARRC* where "*" indicates intrachain disulfide bond between cysteine residues
SEQ ID N°30: *CSNRDARRC* -GG where "*" indicates intrachain disulfide bond between cysteine residues
SEQ ID N031: GG-*CSNRDARRC*-GG- where "*" indicates intrachain disulfide bond between cysteine residues
SEQ ID N°32: GG-*CSNRDARRC* where "*" indicates intrachain disulfide bond between cysteine residues .
2. Pharmaceutical compositions comprising a therapeutically effective amount of at least one peptide such as above defined in association with a pharmaceutically acceptable carrier.
3. The pharmaceutical compositions of claim 2 for the treatment of solid cancers.
4. The pharmaceutical compositions of claim 2, for the treatment of bladder tumors .
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81734506P | 2006-06-30 | 2006-06-30 | |
| US60/817,345 | 2006-06-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2008004130A2 true WO2008004130A2 (en) | 2008-01-10 |
| WO2008004130A3 WO2008004130A3 (en) | 2008-07-31 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2007/002940 WO2008004130A2 (en) | 2006-06-30 | 2007-07-02 | Peptides for targeting the mitochondrial transition pore complex for therapeutic apoptosis induction and biological applications |
Country Status (1)
| Country | Link |
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| WO (1) | WO2008004130A2 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004031768A2 (en) * | 2002-10-02 | 2004-04-15 | Theraptosis S.A. | Method for screening modulators of mitochondrial functioning |
| WO2005030238A1 (en) * | 2003-09-25 | 2005-04-07 | Theraptosis | Peptides having, for example, an antiangiogenic activity and applications thereof in therapeutics |
-
2007
- 2007-07-02 WO PCT/IB2007/002940 patent/WO2008004130A2/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004031768A2 (en) * | 2002-10-02 | 2004-04-15 | Theraptosis S.A. | Method for screening modulators of mitochondrial functioning |
| WO2005030238A1 (en) * | 2003-09-25 | 2005-04-07 | Theraptosis | Peptides having, for example, an antiangiogenic activity and applications thereof in therapeutics |
Non-Patent Citations (1)
| Title |
|---|
| DON A S ET AL: "Mitochondria as cancer drug targets" TRENDS IN MOLECULAR MEDICINE, ELSEVIER CURRENT TRENDS, vol. 10, no. 8, 1 August 2004 (2004-08-01), pages 372-378, XP004552305 ISSN: 1471-4914 * |
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| WO2008004130A3 (en) | 2008-07-31 |
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