WO2024153596A1 - 14-3-3 protein modulators as antitumor agents - Google Patents
14-3-3 protein modulators as antitumor agents Download PDFInfo
- Publication number
- WO2024153596A1 WO2024153596A1 PCT/EP2024/050836 EP2024050836W WO2024153596A1 WO 2024153596 A1 WO2024153596 A1 WO 2024153596A1 EP 2024050836 W EP2024050836 W EP 2024050836W WO 2024153596 A1 WO2024153596 A1 WO 2024153596A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cancer
- compound
- methylbenzenesulfonamide
- oxoindolin
- methyl
- Prior art date
Links
- 102000004899 14-3-3 Proteins Human genes 0.000 title abstract description 21
- 101710112812 14-3-3 protein Proteins 0.000 title abstract description 6
- 229940076155 protein modulator Drugs 0.000 title abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 title description 6
- -1 2-oxoindole compound Chemical class 0.000 claims abstract description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 201000011510 cancer Diseases 0.000 claims abstract description 13
- 206010033701 Papillary thyroid cancer Diseases 0.000 claims abstract description 12
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims abstract description 10
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims abstract description 10
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims abstract description 10
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims abstract description 10
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims abstract description 10
- 206010035226 Plasma cell myeloma Diseases 0.000 claims abstract description 10
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims abstract description 10
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 9
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 9
- 206010027406 Mesothelioma Diseases 0.000 claims abstract description 9
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 208000009018 Medullary thyroid cancer Diseases 0.000 claims abstract description 8
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 claims abstract description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 7
- 201000005202 lung cancer Diseases 0.000 claims abstract description 7
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 7
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical group 0.000 claims abstract description 6
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 6
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims abstract description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims abstract description 5
- 206010005003 Bladder cancer Diseases 0.000 claims abstract description 5
- 208000003174 Brain Neoplasms Diseases 0.000 claims abstract description 5
- 206010014733 Endometrial cancer Diseases 0.000 claims abstract description 5
- 206010014759 Endometrial neoplasm Diseases 0.000 claims abstract description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims abstract description 5
- 208000034578 Multiple myelomas Diseases 0.000 claims abstract description 5
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical group O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims abstract description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 5
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims abstract description 5
- 206010038389 Renal cancer Diseases 0.000 claims abstract description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 5
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims abstract description 5
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 5
- 208000014829 head and neck neoplasm Diseases 0.000 claims abstract description 5
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 5
- 201000010982 kidney cancer Diseases 0.000 claims abstract description 5
- 201000007270 liver cancer Diseases 0.000 claims abstract description 5
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 5
- 208000026037 malignant tumor of neck Diseases 0.000 claims abstract description 5
- 201000000050 myeloid neoplasm Diseases 0.000 claims abstract description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims abstract description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 5
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims abstract description 5
- 201000005112 urinary bladder cancer Diseases 0.000 claims abstract description 5
- 208000032467 Aplastic anaemia Diseases 0.000 claims abstract description 4
- 206010002022 amyloidosis Diseases 0.000 claims abstract description 4
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 63
- FSNPJLVCOUTIGP-PDGQHHTCSA-N 4-methyl-N-[(3Z)-2-oxo-3-(thiophen-2-ylmethylidene)-1H-indol-5-yl]benzenesulfonamide Chemical compound O=C\1NC2=CC=C(C=C2/C/1=C/C=1SC=CC=1)NS(=O)(=O)C1=CC=C(C=C1)C FSNPJLVCOUTIGP-PDGQHHTCSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 208000005017 glioblastoma Diseases 0.000 claims description 9
- DYGARFGUUQRBEB-YVLHZVERSA-N CC(C=C1)=CC=C1S(NC(C=C1/C2=C/C3=CC=NN3)=CC=C1NC/2=O)(=O)=O Chemical compound CC(C=C1)=CC=C1S(NC(C=C1/C2=C/C3=CC=NN3)=CC=C1NC/2=O)(=O)=O DYGARFGUUQRBEB-YVLHZVERSA-N 0.000 claims description 8
- JLXDABATJUEILO-UHFFFAOYSA-N CC(C=C1)=CC=C1S(NC(C=C1C2=CC3=CC=CN=C3N)=CC=C1NC2=O)(=O)=O Chemical compound CC(C=C1)=CC=C1S(NC(C=C1C2=CC3=CC=CN=C3N)=CC=C1NC2=O)(=O)=O JLXDABATJUEILO-UHFFFAOYSA-N 0.000 claims description 6
- GRSGMGATDHNVCF-WJDWOHSUSA-N N(C1=CC=2/C(=C/C=3NC=CN=3)/C(=O)NC=2C=C1)S(=O)(=O)C1=CC=C(C)C=C1 Chemical compound N(C1=CC=2/C(=C/C=3NC=CN=3)/C(=O)NC=2C=C1)S(=O)(=O)C1=CC=C(C)C=C1 GRSGMGATDHNVCF-WJDWOHSUSA-N 0.000 claims description 6
- 102000016252 Huntingtin Human genes 0.000 claims description 5
- 108050004784 Huntingtin Proteins 0.000 claims description 5
- RVDUNBXIZCRPKV-BOPFTXTBSA-N O=C(/C(\C1=C2)=C\C3=CC=CS3)NC1=CC=C2NS(C(C=C1)=CC=C1F)(=O)=O Chemical compound O=C(/C(\C1=C2)=C\C3=CC=CS3)NC1=CC=C2NS(C(C=C1)=CC=C1F)(=O)=O RVDUNBXIZCRPKV-BOPFTXTBSA-N 0.000 claims description 5
- RITDTUJLJYAZNZ-BOPFTXTBSA-N [O-][N+](C(C=C1)=CC=C1S(NC(C=C1/C2=C/C3=CC=CS3)=CC=C1NC/2=O)(=O)=O)=O Chemical compound [O-][N+](C(C=C1)=CC=C1S(NC(C=C1/C2=C/C3=CC=CS3)=CC=C1NC/2=O)(=O)=O)=O RITDTUJLJYAZNZ-BOPFTXTBSA-N 0.000 claims description 5
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 4
- JVGUKDNEYFTXFC-UHFFFAOYSA-N CC(C=C1)=CC=C1S(NC(C=C1C2=C3C(C=CC=C4)=C4C4=CC=CC=C34)=CC=C1NC2=O)(=O)=O Chemical compound CC(C=C1)=CC=C1S(NC(C=C1C2=C3C(C=CC=C4)=C4C4=CC=CC=C34)=CC=C1NC2=O)(=O)=O JVGUKDNEYFTXFC-UHFFFAOYSA-N 0.000 claims description 4
- JAFDYZFTXLLSNT-UHFFFAOYSA-N CC(C=C1)=CC=C1S(NC(C=C1C2=CC3=NC=CN3C)=CC=C1NC2=O)(=O)=O Chemical compound CC(C=C1)=CC=C1S(NC(C=C1C2=CC3=NC=CN3C)=CC=C1NC2=O)(=O)=O JAFDYZFTXLLSNT-UHFFFAOYSA-N 0.000 claims description 4
- ZDGJMKVTPXTCHM-UHFFFAOYSA-N CC1=NC=C(C=C(C2=CC(NS(C3=CC=C(C)C=C3)(=O)=O)=CC=C2N2)C2=O)N1 Chemical compound CC1=NC=C(C=C(C2=CC(NS(C3=CC=C(C)C=C3)(=O)=O)=CC=C2N2)C2=O)N1 ZDGJMKVTPXTCHM-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- MUWCCKZTCBZNND-ATVHPVEESA-N O=C(/C(\C1=C2)=C\C3=CC=CS3)NC1=CC=C2NS(C1=CC=CC=C1)(=O)=O Chemical compound O=C(/C(\C1=C2)=C\C3=CC=CS3)NC1=CC=C2NS(C1=CC=CC=C1)(=O)=O MUWCCKZTCBZNND-ATVHPVEESA-N 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- FSNPJLVCOUTIGP-UHFFFAOYSA-N CC(C=C1)=CC=C1S(NC(C=C1C2=CC3=CC=CS3)=CC=C1NC2=O)(=O)=O Chemical compound CC(C=C1)=CC=C1S(NC(C=C1C2=CC3=CC=CS3)=CC=C1NC2=O)(=O)=O FSNPJLVCOUTIGP-UHFFFAOYSA-N 0.000 claims description 2
- DYGARFGUUQRBEB-UHFFFAOYSA-N CC(C=C1)=CC=C1S(NC(C=C1C2=CC3=CC=NN3)=CC=C1NC2=O)(=O)=O Chemical compound CC(C=C1)=CC=C1S(NC(C=C1C2=CC3=CC=NN3)=CC=C1NC2=O)(=O)=O DYGARFGUUQRBEB-UHFFFAOYSA-N 0.000 claims description 2
- ZNMRFRHUNRJWGZ-UHFFFAOYSA-N CC(C=C1)=CC=C1S(NC(C=C1C2=CC3=CNN=C3)=CC=C1NC2=O)(=O)=O Chemical compound CC(C=C1)=CC=C1S(NC(C=C1C2=CC3=CNN=C3)=CC=C1NC2=O)(=O)=O ZNMRFRHUNRJWGZ-UHFFFAOYSA-N 0.000 claims description 2
- GRSGMGATDHNVCF-UHFFFAOYSA-N CC(C=C1)=CC=C1S(NC(C=C1C2=CC3=NC=CN3)=CC=C1NC2=O)(=O)=O Chemical compound CC(C=C1)=CC=C1S(NC(C=C1C2=CC3=NC=CN3)=CC=C1NC2=O)(=O)=O GRSGMGATDHNVCF-UHFFFAOYSA-N 0.000 claims description 2
- MUWCCKZTCBZNND-UHFFFAOYSA-N O=C(C(C1=C2)=CC3=CC=CS3)NC1=CC=C2NS(C1=CC=CC=C1)(=O)=O Chemical compound O=C(C(C1=C2)=CC3=CC=CS3)NC1=CC=C2NS(C1=CC=CC=C1)(=O)=O MUWCCKZTCBZNND-UHFFFAOYSA-N 0.000 claims description 2
- RITDTUJLJYAZNZ-UHFFFAOYSA-N [O-][N+](C(C=C1)=CC=C1S(NC(C=C1C2=CC3=CC=CS3)=CC=C1NC2=O)(=O)=O)=O Chemical compound [O-][N+](C(C=C1)=CC=C1S(NC(C=C1C2=CC3=CC=CS3)=CC=C1NC2=O)(=O)=O)=O RITDTUJLJYAZNZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
- 108700020469 14-3-3 Proteins 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- ZDGJMKVTPXTCHM-ZDLGFXPLSA-N CC1=NC=C(/C=C(/C2=CC(NS(C3=CC=C(C)C=C3)(=O)=O)=CC=C2N2)\C2=O)N1 Chemical compound CC1=NC=C(/C=C(/C2=CC(NS(C3=CC=C(C)C=C3)(=O)=O)=CC=C2N2)\C2=O)N1 ZDGJMKVTPXTCHM-ZDLGFXPLSA-N 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- JAFDYZFTXLLSNT-SFQUDFHCSA-N 4-methyl-N-[(3E)-3-[(1-methylimidazol-2-yl)methylidene]-2-oxo-1H-indol-5-yl]benzenesulfonamide Chemical compound CN1C(=NC=C1)\C=C/1\C(NC2=CC=C(C=C\12)NS(=O)(=O)C1=CC=C(C=C1)C)=O JAFDYZFTXLLSNT-SFQUDFHCSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 230000004900 autophagic degradation Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 3
- 101000723543 Homo sapiens 14-3-3 protein theta Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- GPWNWKWQOLEVEQ-UHFFFAOYSA-N 2,4-diaminopyrimidine-5-carbaldehyde Chemical compound NC1=NC=C(C=O)C(N)=N1 GPWNWKWQOLEVEQ-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 230000007730 Akt signaling Effects 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 101000600756 Homo sapiens 3-phosphoinositide-dependent protein kinase 1 Proteins 0.000 description 2
- 101001117146 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Proteins 0.000 description 2
- 238000000134 MTT assay Methods 0.000 description 2
- 231100000002 MTT assay Toxicity 0.000 description 2
- QALKNXYDTFSDCP-MFOYZWKCSA-N N-[(3Z)-3-(1H-imidazol-5-ylmethylidene)-2-oxo-1H-indol-5-yl]-4-methylbenzenesulfonamide Chemical compound N1C=NC=C1\C=C\1/C(NC2=CC=C(C=C/12)NS(=O)(=O)C1=CC=C(C=C1)C)=O QALKNXYDTFSDCP-MFOYZWKCSA-N 0.000 description 2
- 102000043276 Oncogene Human genes 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 102100024148 [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Human genes 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960004964 temozolomide Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- HORQAOAYAYGIBM-UHFFFAOYSA-N 2,4-dinitrophenylhydrazine Chemical compound NNC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O HORQAOAYAYGIBM-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- JPUYXUBUJJDJNL-UHFFFAOYSA-N 5-amino-1,3-dihydroindol-2-one Chemical compound NC1=CC=C2NC(=O)CC2=C1 JPUYXUBUJJDJNL-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102000004072 Beclin-1 Human genes 0.000 description 1
- 108090000524 Beclin-1 Proteins 0.000 description 1
- FSNPJLVCOUTIGP-LDADJPATSA-N C1=C(NS(=O)(=O)C2=CC=C(C=C2)C)C=C2/C(=C\C3=CC=CS3)/C(=O)NC2=C1 Chemical compound C1=C(NS(=O)(=O)C2=CC=C(C=C2)C)C=C2/C(=C\C3=CC=CS3)/C(=O)NC2=C1 FSNPJLVCOUTIGP-LDADJPATSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000837845 Homo sapiens Transcription factor E3 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108010057281 Lipocalin 1 Proteins 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 108010058684 R18 peptide Proteins 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 108700025695 Suppressor Genes Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- RITDTUJLJYAZNZ-GZTJUZNOSA-N [O-][N+](C(C=C1)=CC=C1S(NC(C=C1/C2=C\C3=CC=CS3)=CC=C1NC/2=O)(=O)=O)=O Chemical compound [O-][N+](C(C=C1)=CC=C1S(NC(C=C1/C2=C\C3=CC=CS3)=CC=C1NC/2=O)(=O)=O)=O RITDTUJLJYAZNZ-GZTJUZNOSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000008436 biogenesis Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000002701 cell growth assay Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- YLQWCDOCJODRMT-UHFFFAOYSA-N fluoren-9-one Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C2=C1 YLQWCDOCJODRMT-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- YSKZRNFKZLWXRG-ZHTKBQOPSA-N molport-023-276-332 Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(O)=O)C(C)C)NC(=O)[C@H]1NCCC1)C1=CN=CN1 YSKZRNFKZLWXRG-ZHTKBQOPSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 150000005623 oxindoles Chemical class 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000005048 vimentin Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Definitions
- the present invention relates to 14-3-3 protein modulators as antitumor agents.
- 14-3-3 proteins are a family of highly conserved cellular proteins that play key roles in the regulation of central pathways, both in physiological conditions and in diseases, such as cancer and neurodegenerative disorders.
- 14-3-3 target proteins >200 have been identified, including proteins involved in mitogenic signalling, cell survival, cell cycle control, apoptosis, transcriptional regulation, cellular metabolism and cytoskeletal integrity [Tzivion G, Gupta VS, Kaplun L, Balan V: 14-3-3 proteins as potential oncogenes. Seminars in cancer biology 2006, 16:203-213].
- 14-3-3 proteins are known to interact with Beclin-1 and by inhibiting autophagy, they promote the tumorigenesis in lung cancer [Kidd ME, Shumaker DK, Ridge KM: The role of vimentin intermediate filaments in the progression of lung cancer. American journal of respiratory cell and molecular biology 2014, 50:1 -6], glioma, renal cell carcinoma, and cervical cancer. Under certain conditions, the same proteins could activate the autophagic process in glioblastoma and pancreatic.
- 14-3-3 proteins regulate autophagy, which promotes the degradation of accumulated protein [Martina JA, Diab HI, Lishu L, Jeong AL, Patange S, Raben N, Puertollano R: The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris. Science signaling 2014, 7:ra9]. 14-3-3 have been indicated as targets of therapy in 201 1 [Zhao J, Meyerkord CL, Du Y, Khuri FR, Fu H: 14-3-3 proteins as potential therapeutic targets. Seminars in cell & developmental biology 201 1 , 22:705-712] and since then some campaigns of drug discovery took place but up today there are no agents in clinical development. By applying the phage display technology, the R18 peptide was identified to compete with client proteins for the binding to 14-3-3 proteins. R18 is available for research studies and represents the most advanced inhibitor of 14-3-3 proteins.
- the object of the present invention is hence to provide 14-3-3 protein modulators in order to find molecules capable to compete on the binding to 14-3-3 proteins.
- Rapposelli S. et al synthesized small molecules to be used in combination with antitumor drug agents and described it in WO2016/055454 as agents capable to synergize the inhibition of PDK1/Akt signaling pathway.
- N-[(3Z)-3- (1 H-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-1 H-indol-5-yl]-4-methyl- benzenesulfonamide when combined with temozolomide, induced a significant increase in inhibition the glioblastoma cell viability with respect to the single treatment with compound N-[(3Z)-3-(1 H-imidazol-5-ylmethylidene)-2-oxo-2,3- dihydro-1 H-indol-5-yl]-4-methyl-benzenesulfonamide (at all concentration tested) or with temozolomide (example 2 and Figure 3).
- patent publication WO2016/055454 referred to the use of a combination for the treatment of glioblastoma multiforme (GBM), breast tumor and pancreatic tumor together with antitumor agents.
- the present invention concerns a 2-oxoindole compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein
- Ri and R2 are, independently from each other, hydrogen, 1 H-imidazol-2-yl, thienyl and 1 -methyl-1 H-imidazolyl, 2-methyl-1 H-imidazolyl, 2-aminopyridinyl, 1 H- pyrazolyl, with the proviso that one of R1 and R2 is hydrogen; or R1 and R2 together form 9H-fluorene
- R3 is hydrogen, (Ci -C3)alkyl; halogen or NO2 for use in the treatment of a tumor selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, mesothelioma, liver cancer, prostate cancer, endometrium cancer, ovary cancer, stomach cancer, oesophagus cancer, hepatocarcinoma, colorectal cancer, bladder cancer, pancreas cancer, kidney cancer, brain cancer , neck cancer, medullary thyroid cancer, papillary thyroid cancer, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), amyloidosis, Waldenstrom's macroglobulinaemia (WM), aplastic anaemia, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and multiple myeloma (MM).
- a tumor selected from the group consisting of breast cancer, lung cancer
- the present invention concerns a 2-oxoindole compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein
- Ri and R2 are, independently from each other, hydrogen, 1 H-imidazol-2-, thienyl and
- R3 is hydrogen, (Ci-C3)alkyl, halogen or NO2; for use in the treatment of a tumor selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, mesothelioma, liver cancer, prostate cancer, endometrium cancer, ovary cancer , stomach cancer, oesophagus cancer, hepatocarcinoma, colorectal cancer, bladder cancer , pancreas cancer , kidney cancer, brain cancer , neck cancer, medullary thyroid cancer, papillary thyroid cancer, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), amyloidosis, Waldenstrom's macroglobulinaemia (WM), aplastic anaemia, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and multiple myeloma (MM).
- a tumor selected from the group consisting of breast cancer
- the 2-oxoindole compound of Formula (I) or a pharmaceutically acceptable salt thereof is an optimal modulator of 14-3-3 proteins in the treatment of a tumor.
- R1 and R2 are, independently from each other, hydrogen, 1 H-imidazol-2-yl thienyl and 1 -methyl-1 H-imidazolyl, 2-methyl-1 H-imidazolyl, 2-aminopyridinyl, 1 H-pyrazolyl with the proviso that one of R1 and R2 is not hydrogen or R1 and R2 together form 9H-fluorene.
- R1 or R2 is 1 H-pyrazol-2-yl.
- R1 or R2 is 1 H-imidazolyl, more preferably 1 H-imidazol-
- R1 and R2 are thienyl.
- Rs is hydrogen, (Ci-C3)alkyl, halogen or NO2, more preferably R3 can be methyl, ethyl, propyl, isopropyl, fluoro or NO2, still more preferably it is methyl.
- R3 is a methyl in 4 position.
- R3 is halogen it is preferably fluoro in 4-position.
- the compounds of the invention can be in form E and Z with reference to the definition of R1 and R2.
- the compound of formula (I) is selected from the group consisting of (compound FC86)
- FC86 it can be in form E, i.e. N-[(3E)-2-oxo-3-(thiophene-2- ylmethylidene)-2,3-dihydro-1 H-indol-5-yl]-4-methylbenzenesulfonamide) or in form Z, i.e. (N-[(3Z)-2-oxo-3-(thiophene-2-ylmethylidene)-2,3-dihydro-1 H-indol-5-yl]-4- methylbenzenesulfonamide).
- all the compounds can be in E and Z forms, being comprised in the definitions all the stereo-compounds.
- the compound for use of Formula (I) is selected from the group consisting of:
- compound FC86 was extremely active against glioblastoma, hepatocarcinoma, mesothelioma, colorectal cancer, medullary (MTC) thyroid cancer, papillary thyroid cancer (PTC).
- the compounds of Formula (I) are antitumor agents against a tumor selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, mesothelioma, liver cancer, prostate cancer, endometrium cancer, ovary cancer, stomach cancer, oesophagus cancer, hepatocarcinoma, colorectal cancer, bladder cancer, pancreas cancer, kidney cancer, brain cancer, neck cancer, medullary thyroid cancer, papillary thyroid cancer, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), myloidosis, Waldenstrom's macroglobulinaemia (WM), mplastic anaemia, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM).
- a tumor selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, mesothelioma,
- the compounds of the invention showed surprisingly results against mesothelioma, hepatocarcinoma, glioblastoma, medullary (MTC) thyroid cancer, papillary thyroid cancer (PTC) and colorectal cancer.
- the compounds for use of the invention are present in a pharmaceutical composition together with pharmaceutically acceptable carriers and excipients.
- composition hence can comprise also pharmaceutically acceptable excipients and can be administered in a pharmaceutical form suitable for the desired administration route.
- Pharmaceutically acceptable additives can be excipients, ligands, dispersing agents, colorants, humectants, commonly used for the preparation of tablets, capsules, pills, solutions, suspensions, emulsions for oral administration. Injectable solutions are also contemplated for parental administration, comprising subcutaneous, spinal and transdermal administration.
- the compound for use of Formula (I) can be used as free base or in a salt form.
- the salt is a salt selected from the group consisting of hydrochloride, hydrobromide, phosphate, sulphate, hydrogensulphate, alkylsulphonate, arylsulphonate, acetate, citrate, ossalate, maleate, fumarate, succinate, lactate, and tartrate.
- a salt can also be formed between a cation and a negatively charged group. Suitable cations include potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
- substituted ammonium ions examples include those derived from: ethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, piperazine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
- composition comprising the compounds for use according to the present invention is preferably for intra-articular, intravenous, oral, transdermal, intrathecal, intranasal, intraperitoneal or intramuscular administration, more preferably oral administration.
- the compound for use of Formula (I) of the invention is preferably in a dose ranging from 1 nM to 20000 nM, more preferably is in a dose ranging from 1 nM to 600 nM.
- the invention will be now detailed with reference to the preparative examples of the compounds of the invention and examples for testing the antitumor activity with illustrative and not limitative purposes.
- the solvents were all acquired from Sigma-Aldrich I Merck to an analytical degree of purity (> 99%).
- Commercial chemical reagents were acquired from Sigma-Aldrich I Merck, Fluorochem, Tokyo Chemical Industry (TCI), or Alfa Aesar and used without further purification.
- the structure of the compounds and their degree of purity (> 95%) were checked by means of 1 H-NMR and 13C-NMR spectrometry.
- the anhydrous environment necessary in some sensitive reactions, was obtained using nitrogen atmosphere.
- the evaporations were carried out in a rotary vacuum evaporator PC3001 VARIOpro, and sodium sulphate (Na2SO4) was used as the dehydration agent.
- Reaction monitoring was performed by Thin Layer Chromatography (TLC) using 60F254 (Sigma-Aldrich / Merck) silica gel plates adsorbed on aluminum supports.
- Microwave reactions were performed using a Biotage® Initiator + microwave. Filtrations were performed using Celite® 545 (Sigma Aldrich) as the filtering agent. Flash chromatographic column purifications were performed using high purity silica gel: 40-63 pm (Sigma-Aldrich I Merck). Alternatively, it was performed automatically using the Biotage® IsoleraTM Prime instrument. The 1 H-NMR and 13C-NMR spectra were recorded by Bruker Avance 400 instrument, respectively at 400 and 101 MHz.
- FC86 was evaluated against cancer cell lines reported in table 1 ).
- FC86 elicits a significant antiproliferative activity against 3 different papillary thyroid cancer cell lines, one medullary thyroid cancer cell line, one colorectal cancer cell line, one glioblastoma cell line, three different cell lines of hepatocarcinoma and three cell lines of mesothelioma.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a 2-oxoindole compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are, independently from each other, hydrogen, 1H-imidazol-2-yl, thienyl and 1-methyl-1H-imidazolyl, 2- methyl-1H-imidazolyl,2-aminopyridinyl, 1H-pyrazolyl, with the proviso that one of R1 and R2 is hydrogen; or R1 and R2 together form 9H-fluorene R3 is hydrogen, (C1- C3)alkyl, halogen or NO2; for use as a 14-3-3 protein modulator in the treatment of a tumor selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, mesothelioma, liver cancer, prostate cancer, endometrium cancer, ovary cancer, stomach cancer, oesophagus cancer, hepatocarcinoma, colorectal cancer, bladder cancer, pancreas cancer, kidney cancer, brain cancer, neck cancer, medullary thyroid cancer, papillary thyroid cancer, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), amyloidosis, Waldenstrom's macroglobulinaemia (WM), aplastic anaemia, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and multiple myeloma (MM).
Description
14-3-3 PROTEIN MODULATORS AS ANTITUMOR AGENTS
★★★★★ ★★★★★ ★★★★★
DESCRIPTION
FIELD OF THE INVENTION
The present invention relates to 14-3-3 protein modulators as antitumor agents.
BACKGROUND
14-3-3 proteins are a family of highly conserved cellular proteins that play key roles in the regulation of central pathways, both in physiological conditions and in diseases, such as cancer and neurodegenerative disorders. Several 14-3-3 target proteins (>200) have been identified, including proteins involved in mitogenic signalling, cell survival, cell cycle control, apoptosis, transcriptional regulation, cellular metabolism and cytoskeletal integrity [Tzivion G, Gupta VS, Kaplun L, Balan V: 14-3-3 proteins as potential oncogenes. Seminars in cancer biology 2006, 16:203-213]. Importantly, the involvement of 14-3-3 proteins in the regulation of various oncogenes and tumour suppressor genes support its detrimental role in human cancer [Wilker E, Yaffe MB: 14-3-3 Proteins-a focus on cancer and human disease. Journal of molecular and cellular cardiology 2004, 37:633-642], In humans, seven genes codify for seven 14-3-3 proteins, namely alpha/beta, epsilon, eta, gamma, theta, sigma, and zeta/delta. Their expression is common to all human tissues, while the overexpression is mostly associated with cancer's insurgence and correlated with advanced tumour grade.
14-3-3 proteins are known to interact with Beclin-1 and by inhibiting autophagy, they promote the tumorigenesis in lung cancer [Kidd ME, Shumaker DK, Ridge KM: The role of vimentin intermediate filaments in the progression of lung cancer. American journal of respiratory cell and molecular biology 2014, 50:1 -6], glioma, renal cell carcinoma, and cervical cancer. Under certain conditions, the same proteins could activate the autophagic process in glioblastoma and pancreatic. Similarly, in neurodegenerative diseases, 14-3-3 proteins regulate autophagy, which promotes the degradation of accumulated protein [Martina JA, Diab HI, Lishu L, Jeong AL, Patange S, Raben N, Puertollano R: The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris. Science signaling 2014, 7:ra9].
14-3-3 have been indicated as targets of therapy in 201 1 [Zhao J, Meyerkord CL, Du Y, Khuri FR, Fu H: 14-3-3 proteins as potential therapeutic targets. Seminars in cell & developmental biology 201 1 , 22:705-712] and since then some campaigns of drug discovery took place but up today there are no agents in clinical development. By applying the phage display technology, the R18 peptide was identified to compete with client proteins for the binding to 14-3-3 proteins. R18 is available for research studies and represents the most advanced inhibitor of 14-3-3 proteins.
The object of the present invention is hence to provide 14-3-3 protein modulators in order to find molecules capable to compete on the binding to 14-3-3 proteins.
The inventors principally focused their attention on 2-oxoindole derivates, wherein one of the inventors proposed oxoindole derivates and described them as agents able to affect Akt pathway [Sestito S, Nesi G, Daniele S, Martelli A, Digiacomo M, Borghini A, Pietra D, Calderone V, Lapucci A, Falasca M, et al: Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme. European journal of medicinal chemistry 2015, 105:274-288],
In fact, Rapposelli S. et al synthesized small molecules to be used in combination with antitumor drug agents and described it in WO2016/055454 as agents capable to synergize the inhibition of PDK1/Akt signaling pathway. Specifically, N-[(3Z)-3- (1 H-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-1 H-indol-5-yl]-4-methyl- benzenesulfonamide, when combined with temozolomide, induced a significant increase in inhibition the glioblastoma cell viability with respect to the single treatment with compound N-[(3Z)-3-(1 H-imidazol-5-ylmethylidene)-2-oxo-2,3- dihydro-1 H-indol-5-yl]-4-methyl-benzenesulfonamide (at all concentration tested) or with temozolomide (example 2 and Figure 3).
Therefore, the patent publication WO2016/055454 referred to the use of a combination for the treatment of glioblastoma multiforme (GBM), breast tumor and pancreatic tumor together with antitumor agents.
SUMMARY OF THE INVENTION
As it will be clear below with the experimental part, the inventors surprisingly found out that only a small group of 2-oxoindole derivatives were capable to act against a cancer. The 2-oxindole derivatives as a class of 14-3-3 protein modulators were able to affect human specific cancer growth both in vitro and in vivo models.
Therefore, the present invention concerns a 2-oxoindole compound of Formula (I) or a pharmaceutically acceptable salt thereof
wherein
Ri and R2 are, independently from each other, hydrogen, 1 H-imidazol-2-yl, thienyl and 1 -methyl-1 H-imidazolyl, 2-methyl-1 H-imidazolyl, 2-aminopyridinyl, 1 H- pyrazolyl, with the proviso that one of R1 and R2 is hydrogen; or R1 and R2 together form 9H-fluorene
R3 is hydrogen, (Ci -C3)alkyl; halogen or NO2 for use in the treatment of a tumor selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, mesothelioma, liver cancer, prostate cancer, endometrium cancer, ovary cancer, stomach cancer, oesophagus cancer, hepatocarcinoma, colorectal cancer, bladder cancer, pancreas cancer, kidney cancer, brain cancer , neck cancer, medullary thyroid cancer, papillary thyroid cancer, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), amyloidosis, Waldenstrom's macroglobulinaemia (WM), aplastic anaemia, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and multiple myeloma (MM).
The inventors hence found out the compounds of formula (I) were optimal modulators of 14-3-3 proteins in the treatment of a tumor as it will be evident in the detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The present invention concerns a 2-oxoindole compound of Formula (I) or a pharmaceutically acceptable salt thereof
wherein
Ri and R2 are, independently from each other, hydrogen, 1 H-imidazol-2-, thienyl and
1 -methyl-1 H-imidazolyl, 2-methyl-1 H-imidazolyl ,2-aminopyridinyl, 1 H-pyrazolyl, with the proviso that one of R1 and R2 is hydrogen; or R1 and R2 together form 9H- fluorene
R3 is hydrogen, (Ci-C3)alkyl, halogen or NO2; for use in the treatment of a tumor selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, mesothelioma, liver cancer, prostate cancer, endometrium cancer, ovary cancer , stomach cancer, oesophagus cancer, hepatocarcinoma, colorectal cancer, bladder cancer , pancreas cancer , kidney cancer, brain cancer , neck cancer, medullary thyroid cancer, papillary thyroid cancer, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), amyloidosis, Waldenstrom's macroglobulinaemia (WM), aplastic anaemia, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and multiple myeloma (MM).
According to the invention the 2-oxoindole compound of Formula (I) or a pharmaceutically acceptable salt thereof is an optimal modulator of 14-3-3 proteins in the treatment of a tumor.
R1 and R2 are, independently from each other, hydrogen, 1 H-imidazol-2-yl thienyl and 1 -methyl-1 H-imidazolyl, 2-methyl-1 H-imidazolyl, 2-aminopyridinyl, 1 H-pyrazolyl with the proviso that one of R1 and R2 is not hydrogen or R1 and R2 together form 9H-fluorene.
In a preferred embodiment R1 or R2 is 1 H-pyrazol-2-yl.
In a preferred embodiment R1 or R2 is 1 H-imidazolyl, more preferably 1 H-imidazol-
2-yl or 1 H-imidazolyl-5-yl.
In a preferred embodiment one of R1 and R2 is thienyl.
Rs is hydrogen, (Ci-C3)alkyl, halogen or NO2, more preferably R3 can be methyl, ethyl, propyl, isopropyl, fluoro or NO2, still more preferably it is methyl. In an advantageous form R3 is a methyl in 4 position. When R3 is halogen it is preferably fluoro in 4-position.
The compounds of the invention can be in form E and Z with reference to the definition of R1 and R2.
In a preferred embodiment the compound of formula (I) is selected from the group consisting of
(compound FC86)
N-[-2-oxo-3-(thiophene-2-ylmethylidene)-2,3-dihydro-1 H-indol-5-yl]-4- methylbenzenesulfonamide;
(compound FC91 )
N-{-3-[(1 -methyl-1 H-imidazol-2-yl)methylidene]-2-oxo-2,3-dihydro-1 H-indol-5-yl}-4- methylbenzenesulfonamide;
(compound SB14)
4-methyl-N-(3-((2-methyl-1 H-imidazol-5-yl)methylene)-2-oxoindolin-5- yl)benzenesulfonamide;
(compound SB18)
N-(3-((1 H-pyrazol-4-yl)methylene)-2-oxoindolin-5-yl)-4-
methylbenzenesulfonamide;
(compound SB17)
N-(3-((1 H-pyrazol-5-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide;
N-(3-((1 H-imidazol-2-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide;
N-(3-((2-aminopyridin-3-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide;
N-(3-(9H-fluoren-9-ylidene)-2-oxoindolin-5-yl)-4-methylbenzenesulfonamide;
(compound IT 13)-4-fluoro-N-(2-oxo-3-(thiophen-2- ylmethylene)indolin-5-yl)benzenesulfonamide;
(compound IT16)
4-nitro-N-(2-oxo-3-(thiophen-2-ylmethylene)indolin-5-yl)benzenesulfonamide; and
(compound IT15)
N-(2-oxo-3-(thiophen-2-ylmethylene)indolin-5-yl)benzenesulfonamide.
In case of FC86 it can be in form E, i.e. N-[(3E)-2-oxo-3-(thiophene-2- ylmethylidene)-2,3-dihydro-1 H-indol-5-yl]-4-methylbenzenesulfonamide) or in form Z, i.e. (N-[(3Z)-2-oxo-3-(thiophene-2-ylmethylidene)-2,3-dihydro-1 H-indol-5-yl]-4- methylbenzenesulfonamide).
According to the present invention, all the compounds can be in E and Z forms, being comprised in the definitions all the stereo-compounds.
Therefore, in a most preferred embodiment the compound for use of Formula (I) is selected from the group consisting of:
N-[(3Z)-2-oxo-3-(thiophene-2-ylmethylidene)-2,3-dihydro-1 H-indol-5-yl]-4- methylbenzenesulfonamide (compound FC86);
N-{(3E)-3-[(1 -methyl-1 H-imidazol-2-yl)methylidene]-2-oxo-2,3-dihydro-1 H-indol-5- yl}-4-methylbenzenesulfonamide(compound FC91 );
(Z)-4-methyl-N-(3-((2-methyl-1 H-imidazol-5-yl)methylene)-2-oxoindolin-5- yl)benzenesulfonamide(compound SB14);
(E/Z)-N-(3-((1 H-pyrazol-4-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide (compound SB18);
(Z)-N-(3-((1 H-pyrazol-5-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide (compound SB17);
(Z)-N-(3-((1 H-imidazol-2-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide (compound SB19);
N-(3-((2-aminopyridin-3-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide (compound SB20);
N-(3-(9H-fluoren-9-ylidene)-2-oxoindolin-5-yl)-4-methylbenzenesulfonamide
(compound SB21 );
(Z)-4-fluoro-N-(2-oxo-3-(thiophen-2-ylmethylene)indolin-5-yl)benzenesulfonamide (compound IT13);
(Z)-4-nitro-N-(2-oxo-3-(thiophen-2-ylmethylene)indolin-5-yl)benzenesulfonamide (compound IT16); and (Z)-N-(2-oxo-3-(thiophen-2-ylmethylene)indolin-5-yl)benzenesulfonamide (compound IT15).
Preferably compound FC86 was extremely active against glioblastoma, hepatocarcinoma, mesothelioma, colorectal cancer, medullary (MTC) thyroid cancer, papillary thyroid cancer (PTC).
The compounds of Formula (I) are antitumor agents against a tumor selected from the group consisting of breast cancer, lung cancer, non-small cell lung cancer, mesothelioma, liver cancer, prostate cancer, endometrium cancer, ovary cancer, stomach cancer, oesophagus cancer, hepatocarcinoma, colorectal cancer, bladder cancer, pancreas cancer, kidney cancer, brain cancer, neck cancer, medullary thyroid cancer, papillary thyroid cancer, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), myloidosis, Waldenstrom's macroglobulinaemia (WM), mplastic anaemia, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM).
Preferably the compounds of the invention showed surprisingly results against mesothelioma, hepatocarcinoma, glioblastoma, medullary (MTC) thyroid cancer, papillary thyroid cancer (PTC) and colorectal cancer.
Preferably the compounds for use of the invention are present in a pharmaceutical composition together with pharmaceutically acceptable carriers and excipients.
The composition hence can comprise also pharmaceutically acceptable excipients and can be administered in a pharmaceutical form suitable for the desired administration route.
Pharmaceutically acceptable additives can be excipients, ligands, dispersing agents, colorants, humectants, commonly used for the preparation of tablets, capsules, pills, solutions, suspensions, emulsions for oral administration. Injectable solutions are also contemplated for parental administration, comprising subcutaneous, spinal and transdermal administration.
The compound for use of Formula (I) can be used as free base or in a salt form. Preferably, the salt is a salt selected from the group consisting of hydrochloride, hydrobromide, phosphate, sulphate, hydrogensulphate, alkylsulphonate, arylsulphonate, acetate, citrate, ossalate, maleate, fumarate, succinate, lactate, and tartrate. A salt can also be formed between a cation and a negatively charged group. Suitable cations include potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, piperazine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
The pharmaceutical composition comprising the compounds for use according to the present invention is preferably for intra-articular, intravenous, oral, transdermal, intrathecal, intranasal, intraperitoneal or intramuscular administration, more preferably oral administration.
The compound for use of Formula (I) of the invention is preferably in a dose ranging from 1 nM to 20000 nM, more preferably is in a dose ranging from 1 nM to 600 nM. The invention will be now detailed with reference to the preparative examples of the compounds of the invention and examples for testing the antitumor activity with illustrative and not limitative purposes.
EXPERIMENTAL PART
Example 1 Preparation of the 2-oxoindole derivative compounds
In the following experimental part, all the 2-oxoindole derivative compounds were prepared following the indications provided in “Synthesis of new enzyme inhibitors as potential tools for the antineoplastic therapy”-PhD thesis in Drug Science and Bioactive Substances- XXIV cycle- G. Nesi and described in Sestito et al. Eur J med Chem 2015 10.1016/j.ejmech.2O15.10.020.
All the compounds (FC86,FC91 ,SB14,SB18,SB17,SB19, SB20,SB21 ,IT13,IT16 and IT15) were prepared following the synthetic procedure reported in the following scheme 2.
Reagents and Conditions: (a) H2O, 20°C, 2h; (b) appropriate carbaldehyde or ketone, EtOH, pirrolidine, 110°C, 16h.
The condensation reaction of 5-amino-1 ,3-dihydro-2H-indol-2-one with the arylsulfonylchloride provided, A/-(2-oxo-2,3-dihydro-1 /-/-indol-5-yl)-arylsulfonamide. The products obtained were subjected to a condensation reaction with the appropriate aromatic carbaldehydes or fluorenone to provide the desired compounds.
The following 2-oxo-indole derivatives were then prepared:
(compound FC86)
N-[(3Z)-2-oxo-3-(thiophene-2-ylmethylidene)-2,3-dihydro-1 H-indol-5-yl]-4- methylbenzenesulfonamide
(compound FC91 )
N-{(3E)-3-[(1 -methyl-1 H-imidazol-2-yl)methylidene]-2-oxo-2,3-dihydro-1 H-indol-5- yl}-4-methylbenzenesulfonamide.
(compound SB14)
(Z)-4-methyl-N-(3-((2-methyl-1 H-imidazol-5-yl)methylene)-2-oxoindolin-5- yl)benzenesulfonamide
(compound SB18) (E/Z)-N-(3-((1 H-pyrazol-4-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide
(compound SB17)
(Z)-N-(3-((1 H-pyrazol-5-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide
(Z)-N-(3-((1 H-imidazol-2-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide
N-(3-((2-aminopyridin-3-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide
(Z)-4-fluoro-N-(2-oxo-3-(thiophen-2-ylmethylene)indolin-5-yl)benzenesulfonamide
(Z)-N-(2-oxo-3-(thiophen-2-ylmethylene)indolin-5-yl)benzenesulfonamide.
Example 2 Experimental protocols
Chemistry.
The solvents were all acquired from Sigma-Aldrich I Merck to an analytical degree of purity (> 99%). Commercial chemical reagents were acquired from Sigma-Aldrich I Merck, Fluorochem, Tokyo Chemical Industry (TCI), or Alfa Aesar and used without further purification. The structure of the compounds and their degree of purity (> 95%) were checked by means of 1 H-NMR and 13C-NMR spectrometry.
The anhydrous environment, necessary in some sensitive reactions, was obtained using nitrogen atmosphere. The evaporations were carried out in a rotary vacuum evaporator PC3001 VARIOpro, and sodium sulphate (Na2SO4) was used as the dehydration agent. Reaction monitoring was performed by Thin Layer Chromatography (TLC) using 60F254 (Sigma-Aldrich / Merck) silica gel plates
adsorbed on aluminum supports. TLCs were visualized using a UV lamp (Short wave: Amax = 254 nm; Long wave Amax = 365 nm), and \ or PMA (10% phosphomolybdic acid in EtOH), and \ or DNP (6% 2,4- dinitrophenylhydrazine, 60% 1 M H2SO4 in EtOH).
Microwave reactions (MW) were performed using a Biotage® Initiator + microwave. Filtrations were performed using Celite® 545 (Sigma Aldrich) as the filtering agent. Flash chromatographic column purifications were performed using high purity silica gel: 40-63 pm (Sigma-Aldrich I Merck). Alternatively, it was performed automatically using the Biotage® IsoleraTM Prime instrument. The 1 H-NMR and 13C-NMR spectra were recorded by Bruker Avance 400 instrument, respectively at 400 and 101 MHz. The chemical shifts (5) were expressed in ppm using the residual solvent as internal standard (1 H-NMR: CDCI3, 7.26; D2O, 4.79; CD3OD, 3.31 ; DMSO-d6, 2.50; 13C-NMR: CDCI3, 77.0; CD3OD, 49.0; DMSO-d6, 39.5). The coupling constants (J) are reported in Hz with the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s: broad signal.
General procedure for the synthesis of SB14, SB17, SB18, SB19, SB20, SB21 , IT15, IT16, IT13
In a vial, the appropriate arylsulfonamide II (0.165 mmol) is dissolved in EtOH, and then the appropriate carbaldehyde or ketone (0.182 mmol) and a catalytic amount of piperidine are added. The reaction was then stirred at 1 10 °C for 16h or at 140 °C for 10 min in the microwave reactor. After this period, the solvent is removed and the crude obtained was triturated with MeOH. Subsequently, the solid obtained was filtered, giving the desired compound.
SB14: (Z)-4-methyl-N-(3-((2-methyl-1 H-imidazol-5-yl)methylene)-2-oxoindolin-5- yl)benzenesulfonamide
Yield: 18%; 1 H NMR (DMSO-d6): 5 2.32 (s, 3H, CH3); 2.45 (s, 3H, CH3); 6.70-6.80 (m, 2H, Ar); 7.30-7.38 (m, 3H, Ar); 7.57-7.66 (m, 4H, Ar); 9.90 (br s, 1 H, NH); 10.91 (br s, 1 H, NH) ppm.
SB18: (E/Z)-N-(3-((1 H-pyrazol-4-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide (mix 40:60) Yields: 16%
1 HNMR (MeOD): 5 2.33-2.35 (m, 3H, CH3); 6.70 (d, 1 H, J= 8 Hz, Ar, Z-isomer); 6.76-6.82 (m, 2H, Ar); 6.90 (dd, 1 H, J= 8, 1.6 Hz, Ar, Z-isomer); 7.28 (d, 2H, J= 8
Hz, Ar); 7.32 (d, 1 H, J= 1 .6 Hz, Ar); 7.65-7.61 (m, 3H, Ar e CH=); 8.02 (br s, 1 H, Ar); 8.61 (br s, 1 H, NH) ppm.
SB17:(Z)-N-(3-((1 H-pyrazol-5-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide
Purified by chromatography eluting with AcOEt/EP 6:4. Yields: 5%; 1 H NMR (MeOD): S 2.30 (s, 3H, CH3); 6.69 (d, 1 H, J= 2.4 Hz, Ar); 6.74 (d, 1 H, J= 8 Hz, Ar); 6.88-6.90 (m, 1 H, Ar); 7.24 (d, 2H, J= 8.2 Hz, Ar); 7.57 (s, 1 H, CH=); 7.60 (d, 2H, J= 8.2 Hz, Ar), 7.79 (br s, 1 H, Ar); 8.67 (br s, 1 H, Ar) ppm.
13C NMR (MeOD): 5 147.9; 145.0; 144.9; 141.2; 139.5; 139.4; 137.9; 137.7; 132.9; 130.6; 130.5; 129.0; 126.5; 123.6; 1 16.6; 1 12.7; 1 1 1.4; 1 10.7; 21.4 ppm.
SB19: (Z)-N-(3-((1 H-imidazol-2-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide
Yields: 70%; 1 H NMR (DMSO): 5 2.32 (s, 3H, CH3); 6.76 (d, 1 H, J= 8.2 Hz, Ar); 6.88 (dd, 1 H, J= 1 .8, 8.2 Hz, Ar); 7.33 (d, 2H, J= 8.2 Hz, Ar); 7.35 (s, 1 H, CH=); 7.43 (d, 1 H, J= 1 .6 Hz, Ar); 7.55-7.56 (m, 2H, Ar); 7.61 (d, 2H, J= 8.2 Hz, Ar) ppm.
SB20:N-(3-((2-aminopyridin-3-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide
Purified by column chromatography with gradient elution mode using CH3CcanCN/0.1 % Et3N (9:1 :0.1 to 6:4:0.1 )
Yields: 57%;
SB20A (Z-isomer): 1 HNMR (MeOD): 5 2.37 (s, 3H, CH3); 6.66-6.71 (m, 1 H, Py); 6.77 (d, 1 H, J= 8.2 Hz, Ar); 6.95 (dd, 1 H, J= 8.2, 1 ,6 Hz); 7.11 (d, 1 H, J = 1.6 Hz, Ar); 7.25 (d, 2H, J= 8 Hz, Ar); 7.47 (d, 2H, J= 8 Hz, Ar); 7.50 (s, 1 H, CH=), 7.59-7.61 (m, 1 H, Py); 8.06-8.07 (m, 1 H, Py) ppm.;
SB20B (E-isomer): 1 HNMR (MeOD): 5 2.37 (s, 3H, CH3); 6.66-6.71 (m, 2H, Py e Ar); 6.81 (dd, 1 H, J= 8.2, 1 ,6 Hz); 7.29 (d, 2H, J= 8 Hz, Ar); 7.43 (d, 1 H, J= 1 .6 Hz, Ar); 7.47 (d, 2H, J= 8 Hz, Ar); 7.53 (s, 1 H, CH=), 7.96-7.98 (m, 1 H, Py); 8.38-8.40 (m, 1 H, Py) ppm.
SB21 : N-(3-(9H-fluoren-9-ylidene)-2-oxoindolin-5-yl)-4-methylbenzenesulfonamide Purified by column chromatography with gradient elution mode using EP/AcOEt (from 8:2 to 6:4),
Yield: 52%; 1 H NMR (MeOD): 5 2.37 (s, 3H, CH3); 6.77 (d, 1 H, J= 8.2 Hz, Ar); 6.90- 6.92 (m, 1 H, Ar); 7.14 (t, 1 H, J= 7.6 Hz, Ar); 7.20 (t, 1 H, J= 7.6 Hz, Ar), 7.31 (d, 2H,
J= 8 Hz, Ar); 7.36-7.42 (m, 2H, Ar); 7.59 (d, 2H, J= 8 Hz, Ar); 7.64-7.69 (m, 2H, Ar);
7.81 (br s, 1 H, Ar); 8.13 (d, 1 H, J= 8 Hz, Ar); 8.95 (d, 1 H, J= 8 Hz, Ar) ppm.
13C NMR (MeOD): 5 150.8; 145.0; 144.3; 143.1 ; 141.8; 138.8; 138.1 ; 137.9; 132.9; 132.7; 132.2; 130.6; 128.9; 128.8; 128.7; 128.3; 127.6; 125.0; 121.2; 120.6; 1 1 1.4; 21.44 ppm.
IT 15 (E/Z) N-[(3)-2-oxo-3-[(thiophen-2-yl)methylidene]-2,3-dihydro-1 H-indol-5- yl]benzenesulfonamide
Yields 58%; 1 H NMR (Acetone) 5 6.77-6.78 (d, 1 H, J= 8.4 Hz, Ar) 6.89-6.94 (dd, 1 H, J= 8.4, 2 Hz, Ar) 7.21 -7.23 (m, Ar, isom-E) 7.28-7.31 (m, Ar, isom- Z) 7.52-7.53 (m, 2H, Ar) 7.83-7.84 ( d, 1 H, J=5.2 Hz, Ar) 7.80-7.98 (m, 4H) 8.36-8.38 (d, 2H, J=
8.8 Hz, Ar) ppm
IT16: (E/Z) 4-nitro-N-[(3E)-2-oxo-3-[(thiophen-2-yl)methylidene]-2,3-dihydro-1 H- indol-5-yl]benzene-1 -Sulfonamide
Yields 64%; 1 H NMR (Acetone) 5 6.80-6.82 (d, 1 H, J= 8.4 Hz) 6.90-6.93 (dd, 1 H, J= 8.4, 2 Hz) 7.21 -7.29 (m, 1 H, Ar) 7.56-7.57 (d, 1 H, J= 2 Hz, Ar) 7.82-7.84 ( d, 1 H, J=5.2 Hz, Ar) 7.99-7.80 (m, 4H) 8.36-8.38 (d, 2H, J= 8.8 Hz, Ar) ppm
Example 3. Antiproliferative activity of FC86 in cancer cell lines.
FC86 was evaluated against cancer cell lines reported in table 1 ).
Table 1 :
Cell growth assays were performed using MTT assays after 24,48 and 72 h incubation of cells (10 000 per well) with increasing compound concentrations of FC86 in 96-well plates. Dose-response curves were generated by Graph Pad Prism software and IC50 values were calculated as the concentrations causing half- maximal responses relative to control. Data were generated in triplicate and repeated in at least two independent experiments. Data are reported in the following Table 2.
Table 2. IC50 expressed in nM for FC86 after 24, 72 or 96 h of exposure, was calculated by MTT assay (time of exposure to FC86 has been reported in parenthesis
Data collected proved that FC86 elicits a significant antiproliferative activity against 3 different papillary thyroid cancer cell lines, one medullary thyroid cancer cell line, one colorectal cancer cell line, one glioblastoma cell line, three different cell lines of hepatocarcinoma and three cell lines of mesothelioma.
Claims
1. A 2-oxoindole compound of Formula (I) or a pharmaceutically acceptable salt thereof
wherein
Ri and R2 are, independently from each other, hydrogen, 1 H-imidazol-2-yl, thienyl and 1 -methyl-1 H-imidazolyl, 2-methyl-1 H-imidazolyl, 2-aminopyridinyl, 1 H- pyrazolyl, with the proviso that one of R1 and R2 is hydrogen; or R1 and R2 together form 9H-fluorene
R3 is hydrogen, (Ci-C3)alkyl, halogen or NO2; for use in the treatment of a tumor selected from the group consisting of a breast cancer, lung cancer, non-small cell lung cancer, mesothelioma, liver cancer, prostate cancer, endometrium cancer, ovary cancer , stomach cancer, oesophagus cancer, hepatocarcinoma, colorectal cancer, bladder cancer , pancreas cancer , kidney cancer, brain cancer , neck cancer, medullary thyroid cancer, papillary thyroid cancer, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), amyloidosis, Waldenstrom's macroglobulinaemia (WM), aplastic anaemia, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and multiple myeloma (MM).
2. The 2-oxoindole compound for use of claim 1 , wherein one of R1 and R2 is thienyl.
3. The 2-oxoindole compound for use of claim 1 wherein one of R1 and R2 is 1 H- pyrazolyl, preferably 1 H-pyrazol-2-yl or 1 H-pyrazol-5-yl.
4. The 2-oxoindole compound for use of claim 1 wherein one of R1 and R2 is 1 H- imidazolyl, preferably 1 H-imidazol-2-yl.
5. The 2-oxoindole compound for use of anyone of claims 1 -4, wherein R3 is methyl, preferably in 4-position.
6. The 2-oxoindole compound for use of claim 1 wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
(compound FC86) N-[-2-oxo-3-(thiophene-2-ylmethylidene)-2,3-dihydro-1 H-indol-5-yl]-4- methylbenzenesulfonamide;
(compound FC91 )
N-{-3-[(1 -methyl-1 H-imidazol-2-yl)methylidene]-2-oxo-2,3-dihydro-1 H-indol-5-yl}-4- methylbenzenesulfonamide;
(compound SB14)
4-methyl-N-(3-((2-methyl-1 H-imidazol-5-yl)methylene)-2-oxoindolin-5- yl)benzenesulfonamide;
(compound SB18)
N-(3-((1 H-pyrazol-4-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide;
(compound SB17)
N-(3-((1 H-pyrazol-5-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide;
N-(3-((1 H-imidazol-2-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide;
N-(3-((2-aminopyridin-3-yl)methylene)-2-oxoindolin-5-yl)-4-
N-(3-(9H-fluoren-9-ylidene)-2-oxoindolin-5-yl)-4-methylbenzenesulfonamide;
4-nitro-N-(2-oxo-3-(thiophen-2-ylmethylene)indolin-5-yl)benzenesulfonamide; and
N-(2-oxo-3-(thiophen-2-ylmethylene)indolin-5-yl)benzenesulfonamide.
7. The 2-oxoindole compound for use of claim 1 wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
N-[(3Z)-2-oxo-3-(thiophene-2-ylmethylidene)-2,3-dihydro-1 H-indol-5-yl]-4- methylbenzenesulfonamide (compound FC86);
N-{(3E)-3-[(1 -methyl-1 H-imidazol-2-yl)methylidene]-2-oxo-2,3-dihydro-1 H-indol-5- yl}-4-methylbenzenesulfonamide(compound FC91 );
(Z)-4-methyl-N-(3-((2-methyl-1 H-imidazol-5-yl)methylene)-2-oxoindolin-5- yl)benzenesulfonamide(compound SB14);
(E/Z)-N-(3-((1 H-pyrazol-4-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide (compound SB18);
(Z)-N-(3-((1 H-pyrazol-5-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide (compound SB17);
(Z)-N-(3-((1 H-imidazol-2-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide (compound SB19);
N-(3-((2-aminopyridin-3-yl)methylene)-2-oxoindolin-5-yl)-4- methylbenzenesulfonamide (compound SB20);
N-(3-(9H-fluoren-9-ylidene)-2-oxoindolin-5-yl)-4-methylbenzenesulfonamide (compound SB21 );
(Z)-4-fluoro-N-(2-oxo-3-(thiophen-2-ylmethylene)indolin-5-yl)benzenesulfonamide (compound IT13);
(Z)-4-nitro-N-(2-oxo-3-(thiophen-2-ylmethylene)indolin-5-yl)benzenesulfonamide
(compound IT16); and (Z)-N-(2-oxo-3-(thiophen-2-ylmethylene)indolin-5-yl)benzenesulfonamide (compound IT15).
8. The 2-oxoindole compound for use of claim 7 or 8 wherein the compound is
(compound FC86)
N-[(3Z)-2-oxo-3-(thiophene-2-ylmethylidene)-2,3-dihydro-1 H-indol-5-yl]-4- methylbenzenesulfonamide.
9. The 2-oxoindole compound for use of anyone of claims 1 -8, wherein the tumor is selected from the group consisting of mesothelioma, hepatocarcinoma, glioblastoma, papillary thyroid cancer (PTC), medullary thyroid cancer (MTC) and colorectal cancer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT202300000831 | 2023-01-20 | ||
| IT102023000000831 | 2023-01-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2024153596A1 true WO2024153596A1 (en) | 2024-07-25 |
Family
ID=85685169
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2024/050836 WO2024153596A1 (en) | 2023-01-20 | 2024-01-16 | 14-3-3 protein modulators as antitumor agents |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2024153596A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008145398A1 (en) * | 2007-06-01 | 2008-12-04 | Pfizer Italia S.R.L. | 4-arylpyrrole substituted 2-indoline derivatives active as protein kinase inhibitors |
| WO2016055454A1 (en) | 2014-10-06 | 2016-04-14 | International Society For Drug Development S.R.L. | Pharmaceutical combination for the treatment of tumors |
| JP2017043616A (en) * | 2015-08-27 | 2017-03-02 | 学校法人慶應義塾 | 14-3-3 Protein activity regulator |
| CN113773242A (en) * | 2020-06-10 | 2021-12-10 | 兰州大学 | Indol-2-one BRD4 inhibitor and preparation and application thereof |
| WO2023001942A1 (en) * | 2021-07-22 | 2023-01-26 | Simona Rapposelli | 14-3-3 protein modulators as antitumor agents |
-
2024
- 2024-01-16 WO PCT/EP2024/050836 patent/WO2024153596A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008145398A1 (en) * | 2007-06-01 | 2008-12-04 | Pfizer Italia S.R.L. | 4-arylpyrrole substituted 2-indoline derivatives active as protein kinase inhibitors |
| WO2016055454A1 (en) | 2014-10-06 | 2016-04-14 | International Society For Drug Development S.R.L. | Pharmaceutical combination for the treatment of tumors |
| JP2017043616A (en) * | 2015-08-27 | 2017-03-02 | 学校法人慶應義塾 | 14-3-3 Protein activity regulator |
| CN113773242A (en) * | 2020-06-10 | 2021-12-10 | 兰州大学 | Indol-2-one BRD4 inhibitor and preparation and application thereof |
| WO2023001942A1 (en) * | 2021-07-22 | 2023-01-26 | Simona Rapposelli | 14-3-3 protein modulators as antitumor agents |
Non-Patent Citations (10)
| Title |
|---|
| "Synthesis of new enzyme inhibitors as potential tools for the antineoplastic therapy", PHD THESIS IN DRUG SCIENCE AND BIOACTIVE SUBSTANCES |
| JING ZHAO ET AL: "14-3-3 proteins as potential therapeutic targets", SEMINARS IN CELL AND DEVELOPMENTAL BIOLOGY, vol. 22, no. 7, 1 October 2011 (2011-10-01), pages 705 - 712, XP028332074, ISSN: 1084-9521, [retrieved on 20111001], DOI: 10.1016/J.SEMCDB.2011.09.012 * |
| KIDD MESHUMAKER DKRIDGE KM: "The role of vimentin intermediate filaments in the progression of lung cancer", AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, vol. 50, 2014, pages 1 - 6 |
| MARTINA JADIAB HILISHU LJEONG ALPATANGE SRABEN NPUERTOLLANO R: "The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris", SCIENCE SIGNALING, vol. 7, 2014, pages ra9 |
| SESTITO ET AL., EUR J MED CHEM, 2015 |
| SESTITO SNESI GDANIELE SMARTELLI ADIGIACOMO MBORGHINI APIETRA DCALDERONE VLAPUCCI AFALASCA M ET AL.: "Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 105, 2015, pages 274 - 288, XP029290688, DOI: 10.1016/j.ejmech.2015.10.020 |
| TZIVION G ET AL: "14-3-3 proteins as potential oncogenes", SEMINARS IN CANCER BIOLOGY, SAUNDERS SCIENTIFIC PUBLICATIONS, PHILADELPHIA, PA, US, vol. 16, no. 3, 1 June 2006 (2006-06-01), pages 203 - 213, XP024908065, ISSN: 1044-579X, [retrieved on 20060601], DOI: 10.1016/J.SEMCANCER.2006.03.004 * |
| TZIVION GGUPTA VSKAPLUN LBALAN V: "14-3-3 proteins as potential oncogenes", SEMINARS IN CANCER BIOLOGY, vol. 16, 2006, pages 203 - 213, XP024908065, DOI: 10.1016/j.semcancer.2006.03.004 |
| WILKER EYAFFE MB: "14-3-3 Proteins--a focus on cancer and human disease", JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, vol. 37, 2004, pages 633 - 642, XP004537247, DOI: 10.1016/j.yjmcc.2004.04.015 |
| ZHAO JMEYERKORD CLDU YKHURI FRFU H: "14-3-3 proteins as potential therapeutic targets", SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, vol. 22, 2011, pages 705 - 712, XP028332074, DOI: 10.1016/j.semcdb.2011.09.012 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3102202A1 (en) | Neurodegenerative therapies | |
| WO2017206962A1 (en) | Novel inhibitor for flt3 kinase and uses thereof | |
| WO2023001942A1 (en) | 14-3-3 protein modulators as antitumor agents | |
| JP7069031B2 (en) | Combination therapy for proliferative disorders | |
| CN113825752A (en) | Proteolytic targeting chimeras | |
| JP2009519990A (en) | Inhibitor of CCR9 activity | |
| CN101573337B (en) | 5, 6, or 7-substituted-3-(hetero)arylisoquinolinamine derivatives as antineoplastic agents | |
| AU2006233164B2 (en) | Inhibitors of Cdc25 phosphatases | |
| WO2024153596A1 (en) | 14-3-3 protein modulators as antitumor agents | |
| JP2002526450A (en) | CHK1 kinase inhibitor | |
| CN111164087B (en) | Compounds useful for inhibition of human trefoil factor 3 | |
| WO2013052465A1 (en) | [1,3]dioxolo[4,5-g]quinoline-6(5h)thione and [1,3]dioxolo[4,5-g][1,2,4]triazolo[1,5-a]quinoline derivatives as inhibitors of the late sv40 factor (lsf) for use in treating cancer | |
| JP2022520907A (en) | NURR1 receptor regulator | |
| JP2004035485A (en) | Telomerase inhibitor | |
| CN109384793A (en) | A kind of sulfur alcohol compound and its application with HDAC6 inhibitory activity | |
| CN111454278B (en) | PAK1 inhibitor, synthesis thereof and application thereof in preparation of antitumor drugs | |
| WO2017192665A1 (en) | Inhibitors of ires-mediated protein synthesis | |
| JPWO2003024950A1 (en) | Coumarin derivatives | |
| CN112912078B (en) | Combination therapy for the treatment of estrogen receptor positive breast cancer | |
| EP4161916A1 (en) | Substituted isoquinolinylmethyl amides, analogues thereof, and methods using same | |
| WO2022055926A1 (en) | Compositions and methods for treating muscular dystrophies | |
| TWI406853B (en) | Dual inhibitors of egfr and vegfr-2 and uses and production processes thereof | |
| JP2004035486A (en) | Para-phenylenediamine derivative | |
| JP2004035484A (en) | Cyclohexanediamine derivative |