IL274663B2 - Cancer therapy by degrading dual mek signaling - Google Patents
Cancer therapy by degrading dual mek signalingInfo
- Publication number
- IL274663B2 IL274663B2 IL274663A IL27466320A IL274663B2 IL 274663 B2 IL274663 B2 IL 274663B2 IL 274663 A IL274663 A IL 274663A IL 27466320 A IL27466320 A IL 27466320A IL 274663 B2 IL274663 B2 IL 274663B2
- Authority
- IL
- Israel
- Prior art keywords
- active agent
- cancer
- pac
- composition
- mek
- Prior art date
Links
- 230000009977 dual effect Effects 0.000 title 1
- 238000011275 oncology therapy Methods 0.000 title 1
- 230000011664 signaling Effects 0.000 title 1
- 239000013543 active substance Substances 0.000 claims 31
- 150000001875 compounds Chemical class 0.000 claims 19
- 239000000203 mixture Substances 0.000 claims 17
- 206010028980 Neoplasm Diseases 0.000 claims 14
- 201000011510 cancer Diseases 0.000 claims 14
- 239000003112 inhibitor Substances 0.000 claims 7
- 229960003278 osimertinib Drugs 0.000 claims 6
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical group COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 claims 6
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 claims 4
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 claims 4
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims 4
- 229960001602 ceritinib Drugs 0.000 claims 4
- VERWOWGGCGHDQE-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 VERWOWGGCGHDQE-UHFFFAOYSA-N 0.000 claims 4
- 229960002411 imatinib Drugs 0.000 claims 4
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims 4
- 102100023266 Dual specificity mitogen-activated protein kinase kinase 2 Human genes 0.000 claims 3
- 101710146529 Dual specificity mitogen-activated protein kinase kinase 2 Proteins 0.000 claims 3
- 102000001291 MAP Kinase Kinase Kinase Human genes 0.000 claims 3
- 108060006687 MAP kinase kinase kinase Proteins 0.000 claims 3
- 102000001253 Protein Kinase Human genes 0.000 claims 3
- 238000006731 degradation reaction Methods 0.000 claims 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims 3
- 230000002401 inhibitory effect Effects 0.000 claims 3
- 238000000034 method Methods 0.000 claims 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims 3
- 230000026731 phosphorylation Effects 0.000 claims 3
- 238000006366 phosphorylation reaction Methods 0.000 claims 3
- 108060006633 protein kinase Proteins 0.000 claims 3
- 208000003174 Brain Neoplasms Diseases 0.000 claims 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 2
- 229940124647 MEK inhibitor Drugs 0.000 claims 2
- 108700027649 Mitogen-Activated Protein Kinase 3 Proteins 0.000 claims 2
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 claims 2
- 108700015928 Mitogen-activated protein kinase 13 Proteins 0.000 claims 2
- 102100024192 Mitogen-activated protein kinase 3 Human genes 0.000 claims 2
- 206010038389 Renal cancer Diseases 0.000 claims 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 2
- 229960001686 afatinib Drugs 0.000 claims 2
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 claims 2
- 230000006907 apoptotic process Effects 0.000 claims 2
- 239000002774 b raf kinase inhibitor Substances 0.000 claims 2
- 230000015556 catabolic process Effects 0.000 claims 2
- 239000003085 diluting agent Substances 0.000 claims 2
- 239000003623 enhancer Substances 0.000 claims 2
- 206010017758 gastric cancer Diseases 0.000 claims 2
- 230000001939 inductive effect Effects 0.000 claims 2
- 201000010982 kidney cancer Diseases 0.000 claims 2
- 208000032839 leukemia Diseases 0.000 claims 2
- 201000005202 lung cancer Diseases 0.000 claims 2
- 208000020816 lung neoplasm Diseases 0.000 claims 2
- 201000001441 melanoma Diseases 0.000 claims 2
- 230000001394 metastastic effect Effects 0.000 claims 2
- 206010061289 metastatic neoplasm Diseases 0.000 claims 2
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 claims 2
- 201000011549 stomach cancer Diseases 0.000 claims 2
- 229920000858 Cyclodextrin Polymers 0.000 claims 1
- 102000043136 MAP kinase family Human genes 0.000 claims 1
- 108091054455 MAP kinase family Proteins 0.000 claims 1
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- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- 239000011230 binding agent Substances 0.000 claims 1
- 229950003054 binimetinib Drugs 0.000 claims 1
- ACWZRVQXLIRSDF-UHFFFAOYSA-N binimetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1F ACWZRVQXLIRSDF-UHFFFAOYSA-N 0.000 claims 1
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- RESIMIUSNACMNW-BXRWSSRYSA-N cobimetinib fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F RESIMIUSNACMNW-BXRWSSRYSA-N 0.000 claims 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims 1
- 229960002465 dabrafenib Drugs 0.000 claims 1
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 claims 1
- 230000000593 degrading effect Effects 0.000 claims 1
- 230000003111 delayed effect Effects 0.000 claims 1
- 239000007884 disintegrant Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229950001969 encorafenib Drugs 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- 238000001727 in vivo Methods 0.000 claims 1
- CMJCXYNUCSMDBY-ZDUSSCGKSA-N lgx818 Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 CMJCXYNUCSMDBY-ZDUSSCGKSA-N 0.000 claims 1
- 239000002502 liposome Substances 0.000 claims 1
- 239000000314 lubricant Substances 0.000 claims 1
- 239000000693 micelle Substances 0.000 claims 1
- 230000035772 mutation Effects 0.000 claims 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims 1
- 102000020233 phosphotransferase Human genes 0.000 claims 1
- 229920001223 polyethylene glycol Polymers 0.000 claims 1
- 239000003755 preservative agent Substances 0.000 claims 1
- 230000002335 preservative effect Effects 0.000 claims 1
- 230000035755 proliferation Effects 0.000 claims 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims 1
- 230000019491 signal transduction Effects 0.000 claims 1
- 239000002594 sorbent Substances 0.000 claims 1
- 229960001295 tocopherol Drugs 0.000 claims 1
- 229930003799 tocopherol Natural products 0.000 claims 1
- 235000010384 tocopherol Nutrition 0.000 claims 1
- 239000011732 tocopherol Substances 0.000 claims 1
- 229960004066 trametinib Drugs 0.000 claims 1
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical group CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 claims 1
- 239000003981 vehicle Substances 0.000 claims 1
- 229960003862 vemurafenib Drugs 0.000 claims 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical group CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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| SG11202004384YA (en) * | 2017-11-17 | 2020-06-29 | Univ Illinois | Cancer therapy by degrading dual mek signaling |
| KR20210084442A (ko) * | 2018-10-05 | 2021-07-07 | 더 보오드 오브 트러스티스 오브 더 유니버시티 오브 일리노이즈 | 포도막 흑색종 치료를 위한 병용 요법 |
| KR20220016104A (ko) * | 2019-05-30 | 2022-02-08 | 더 보오드 오브 트러스티스 오브 더 유니버시티 오브 일리노이즈 | 암 치료를 위한 프로카스파아제-3 활성화 및 면역요법 |
| WO2023006088A1 (zh) * | 2021-07-30 | 2023-02-02 | 浙江大学智能创新药物研究院 | 一种用于egfr激酶抑制剂的化合物、组合物及其应用 |
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