JP2020519581A - 肥満細胞疾患の処置のための方法及び医薬組成物 - Google Patents
肥満細胞疾患の処置のための方法及び医薬組成物 Download PDFInfo
- Publication number
- JP2020519581A JP2020519581A JP2019561135A JP2019561135A JP2020519581A JP 2020519581 A JP2020519581 A JP 2020519581A JP 2019561135 A JP2019561135 A JP 2019561135A JP 2019561135 A JP2019561135 A JP 2019561135A JP 2020519581 A JP2020519581 A JP 2020519581A
- Authority
- JP
- Japan
- Prior art keywords
- mast cell
- disease
- kit
- hedgehog
- rosa
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 18
- 208000035268 Mast Cell Activation disease Diseases 0.000 title claims abstract description 9
- 238000011282 treatment Methods 0.000 title description 17
- 239000008194 pharmaceutical composition Substances 0.000 title description 5
- 210000003630 histaminocyte Anatomy 0.000 claims abstract description 75
- 239000003112 inhibitor Substances 0.000 claims abstract description 27
- 241000289669 Erinaceus europaeus Species 0.000 claims abstract 4
- 241000027355 Ferocactus setispinus Species 0.000 claims abstract 4
- KVQOGDQTWWCZFX-UHFFFAOYSA-N 2-[[3-[[2-(dimethylamino)phenyl]methyl]-2-pyridin-4-yl-1,3-diazinan-1-yl]methyl]-N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1CN1C(C=2C=CN=CC=2)N(CC=2C(=CC=CC=2)N(C)C)CCC1 KVQOGDQTWWCZFX-UHFFFAOYSA-N 0.000 claims description 32
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 claims description 21
- 239000002067 L01XE06 - Dasatinib Substances 0.000 claims description 21
- 229960002448 dasatinib Drugs 0.000 claims description 21
- 201000008736 Systemic mastocytosis Diseases 0.000 claims description 20
- 208000008585 mastocytosis Diseases 0.000 claims description 16
- 230000035772 mutation Effects 0.000 claims description 13
- -1 Buribanibu Chemical compound 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 208000003251 Pruritus Diseases 0.000 claims description 6
- BMGQWWVMWDBQGC-UHFFFAOYSA-N LSM-1221 Chemical compound C1C(N2C3=CC=CC=C3C3=C4C(=O)NCC4=C4C5=CC=CC=C5N5C4=C32)OC5(C)C(OC)C1N(C)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-UHFFFAOYSA-N 0.000 claims description 5
- 208000029081 mast cell activation syndrome Diseases 0.000 claims description 5
- 208000015943 Coeliac disease Diseases 0.000 claims description 4
- 208000006343 Cutaneous Mastocytosis Diseases 0.000 claims description 4
- 208000004232 Enteritis Diseases 0.000 claims description 4
- 208000005615 Interstitial Cystitis Diseases 0.000 claims description 4
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 4
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 claims description 4
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 claims description 4
- 208000024376 chronic urticaria Diseases 0.000 claims description 4
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 4
- 229960002411 imatinib Drugs 0.000 claims description 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 description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- QQWUGDVOUVUTOY-UHFFFAOYSA-N 5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1S(=O)(=O)C(C)C QQWUGDVOUVUTOY-UHFFFAOYSA-N 0.000 claims description 3
- 206010002198 Anaphylactic reaction Diseases 0.000 claims description 3
- 206010014950 Eosinophilia Diseases 0.000 claims description 3
- 208000005577 Gastroenteritis Diseases 0.000 claims description 3
- 208000002193 Pain Diseases 0.000 claims description 3
- 230000036783 anaphylactic response Effects 0.000 claims description 3
- 208000003455 anaphylaxis Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 230000006552 constitutive activation Effects 0.000 claims description 3
- 230000002327 eosinophilic effect Effects 0.000 claims description 3
- 210000003734 kidney Anatomy 0.000 claims description 3
- 210000004185 liver Anatomy 0.000 claims description 3
- 210000003491 skin Anatomy 0.000 claims description 3
- 208000017520 skin disease Diseases 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- UYJNQQDJUOUFQJ-UHFFFAOYSA-N 2-[[5-chloro-2-[2-methoxy-4-(4-morpholinyl)anilino]-4-pyrimidinyl]amino]-N-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=NC(NC=2C(=CC(=CC=2)N2CCOCC2)OC)=NC=C1Cl UYJNQQDJUOUFQJ-UHFFFAOYSA-N 0.000 claims description 2
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 claims description 2
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 2
- 208000032671 Allergic granulomatous angiitis Diseases 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 208000028185 Angioedema Diseases 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 206010003805 Autism Diseases 0.000 claims description 2
- 208000020706 Autistic disease Diseases 0.000 claims description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 2
- 206010058019 Cancer Pain Diseases 0.000 claims description 2
- 239000005461 Canertinib Substances 0.000 claims description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 2
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 claims description 2
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 206010010539 Congenital megacolon Diseases 0.000 claims description 2
- 206010011796 Cystitis interstitial Diseases 0.000 claims description 2
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 2
- 206010014954 Eosinophilic fasciitis Diseases 0.000 claims description 2
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 claims description 2
- 206010064212 Eosinophilic oesophagitis Diseases 0.000 claims description 2
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 2
- 208000001640 Fibromyalgia Diseases 0.000 claims description 2
- 206010016654 Fibrosis Diseases 0.000 claims description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 208000004592 Hirschsprung disease Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 2
- 239000005536 L01XE08 - Nilotinib Substances 0.000 claims description 2
- 239000002118 L01XE12 - Vandetanib Substances 0.000 claims description 2
- 239000002145 L01XE14 - Bosutinib Substances 0.000 claims description 2
- 239000002146 L01XE16 - Crizotinib Substances 0.000 claims description 2
- UIARLYUEJFELEN-LROUJFHJSA-N LSM-1231 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 claims description 2
- 208000019695 Migraine disease Diseases 0.000 claims description 2
- 208000009525 Myocarditis Diseases 0.000 claims description 2
- GCIKSSRWRFVXBI-UHFFFAOYSA-N N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide Chemical compound C1CN(C)CCN1C1=CC(NC2=NNC(C)=C2)=NC(SC=2C=CC(NC(=O)C3CC3)=CC=2)=N1 GCIKSSRWRFVXBI-UHFFFAOYSA-N 0.000 claims description 2
- 206010033645 Pancreatitis Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 208000031732 Post-Lyme Disease Syndrome Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 239000005463 Tandutinib Substances 0.000 claims description 2
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 claims description 2
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 claims description 2
- 239000004012 Tofacitinib Substances 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 206010052568 Urticaria chronic Diseases 0.000 claims description 2
- 206010047115 Vasculitis Diseases 0.000 claims description 2
- 229960001686 afatinib Drugs 0.000 claims description 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 description 2
- 229960001445 alitretinoin Drugs 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 201000008937 atopic dermatitis Diseases 0.000 claims description 2
- 229960003005 axitinib Drugs 0.000 claims description 2
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 claims description 2
- 229960002938 bexarotene Drugs 0.000 claims description 2
- XQVVPGYIWAGRNI-JOCHJYFZSA-N bi-2536 Chemical compound N1([C@@H](C(N(C)C2=CN=C(NC=3C(=CC(=CC=3)C(=O)NC3CCN(C)CC3)OC)N=C21)=O)CC)C1CCCC1 XQVVPGYIWAGRNI-JOCHJYFZSA-N 0.000 claims description 2
- 210000004204 blood vessel Anatomy 0.000 claims description 2
- 210000000988 bone and bone Anatomy 0.000 claims description 2
- 229960003736 bosutinib Drugs 0.000 claims description 2
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 claims description 2
- 210000004556 brain Anatomy 0.000 claims description 2
- 229950002826 canertinib Drugs 0.000 claims description 2
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 claims description 2
- 208000015114 central nervous system disease Diseases 0.000 claims description 2
- 230000002490 cerebral effect Effects 0.000 claims description 2
- 208000030949 chronic idiopathic urticaria Diseases 0.000 claims description 2
- 206010072757 chronic spontaneous urticaria Diseases 0.000 claims description 2
- 230000007882 cirrhosis Effects 0.000 claims description 2
- 206010009887 colitis Diseases 0.000 claims description 2
- 229960005061 crizotinib Drugs 0.000 claims description 2
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 claims description 2
- 201000001981 dermatomyositis Diseases 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 201000000708 eosinophilic esophagitis Diseases 0.000 claims description 2
- 229960005167 everolimus Drugs 0.000 claims description 2
- 229950005309 fostamatinib Drugs 0.000 claims description 2
- GKDRMWXFWHEQQT-UHFFFAOYSA-N fostamatinib Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C(NC=3N=C4N(COP(O)(O)=O)C(=O)C(C)(C)OC4=CC=3)C(F)=CN=2)=C1 GKDRMWXFWHEQQT-UHFFFAOYSA-N 0.000 claims description 2
- 229960002584 gefitinib Drugs 0.000 claims description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 2
- 210000002216 heart Anatomy 0.000 claims description 2
- 208000006454 hepatitis Diseases 0.000 claims description 2
- 231100000283 hepatitis Toxicity 0.000 claims description 2
- 208000013601 idiopathic anaphylaxis Diseases 0.000 claims description 2
- 206010021247 idiopathic urticaria Diseases 0.000 claims description 2
- 210000000936 intestine Anatomy 0.000 claims description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 2
- 230000000302 ischemic effect Effects 0.000 claims description 2
- 229960004891 lapatinib Drugs 0.000 claims description 2
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims description 2
- 229950001845 lestaurtinib Drugs 0.000 claims description 2
- 206010025135 lupus erythematosus Diseases 0.000 claims description 2
- 208000030159 metabolic disease Diseases 0.000 claims description 2
- 206010027599 migraine Diseases 0.000 claims description 2
- 229950003968 motesanib Drugs 0.000 claims description 2
- RAHBGWKEPAQNFF-UHFFFAOYSA-N motesanib Chemical compound C=1C=C2C(C)(C)CNC2=CC=1NC(=O)C1=CC=CN=C1NCC1=CC=NC=C1 RAHBGWKEPAQNFF-UHFFFAOYSA-N 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 210000003205 muscle Anatomy 0.000 claims description 2
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 claims description 2
- 208000031225 myocardial ischemia Diseases 0.000 claims description 2
- 229950008835 neratinib Drugs 0.000 claims description 2
- ZNHPZUKZSNBOSQ-BQYQJAHWSA-N neratinib Chemical compound C=12C=C(NC\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZNHPZUKZSNBOSQ-BQYQJAHWSA-N 0.000 claims description 2
- 208000004296 neuralgia Diseases 0.000 claims description 2
- 229960001346 nilotinib Drugs 0.000 claims description 2
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims description 2
- 210000000496 pancreas Anatomy 0.000 claims description 2
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 201000007608 radiation cystitis Diseases 0.000 claims description 2
- 201000002793 renal fibrosis Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 208000007056 sickle cell anemia Diseases 0.000 claims description 2
- 229960003787 sorafenib Drugs 0.000 claims description 2
- 229960001796 sunitinib Drugs 0.000 claims description 2
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 2
- UXXQOJXBIDBUAC-UHFFFAOYSA-N tandutinib Chemical compound COC1=CC2=C(N3CCN(CC3)C(=O)NC=3C=CC(OC(C)C)=CC=3)N=CN=C2C=C1OCCCN1CCCCC1 UXXQOJXBIDBUAC-UHFFFAOYSA-N 0.000 claims description 2
- 229950009893 tandutinib Drugs 0.000 claims description 2
- 229960000235 temsirolimus Drugs 0.000 claims description 2
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 claims description 2
- 229960001350 tofacitinib Drugs 0.000 claims description 2
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 claims description 2
- 229950000185 tozasertib Drugs 0.000 claims description 2
- 230000001052 transient effect Effects 0.000 claims description 2
- 229960000241 vandetanib Drugs 0.000 claims description 2
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 claims description 2
- 230000029663 wound healing Effects 0.000 claims description 2
- 239000003798 L01XE11 - Pazopanib Substances 0.000 claims 2
- 229960000639 pazopanib Drugs 0.000 claims 2
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 claims 2
- KOQIAZNBAWFSQM-UHFFFAOYSA-N 2-[4-(3-ethynylanilino)-7-(2-methoxyethoxy)quinazolin-6-yl]oxyethanol Chemical compound C=12C=C(OCCO)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 KOQIAZNBAWFSQM-UHFFFAOYSA-N 0.000 claims 1
- FGTCROZDHDSNIO-UHFFFAOYSA-N 3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(=O)C1=C(NCC=2C3=CC=CC=C3N=CC=2)C=CS1 FGTCROZDHDSNIO-UHFFFAOYSA-N 0.000 claims 1
- SRSGVKWWVXWSJT-ATVHPVEESA-N 5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-n-(2-pyrrolidin-1-ylethyl)-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C(C)C=1C(=O)NCCN1CCCC1 SRSGVKWWVXWSJT-ATVHPVEESA-N 0.000 claims 1
- LLVZBTWPGQVVLW-SNAWJCMRSA-N CP-724714 Chemical compound C12=CC(/C=C/CNC(=O)COC)=CC=C2N=CN=C1NC(C=C1C)=CC=C1OC1=CC=C(C)N=C1 LLVZBTWPGQVVLW-SNAWJCMRSA-N 0.000 claims 1
- 206010064147 Gastrointestinal inflammation Diseases 0.000 claims 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims 1
- 208000006011 Stroke Diseases 0.000 claims 1
- 239000003819 Toceranib Substances 0.000 claims 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims 1
- JROFGZPOBKIAEW-HAQNSBGRSA-N chembl3120215 Chemical compound N1C=2C(OC)=CC=CC=2C=C1C(=C1C(N)=NC=NN11)N=C1[C@H]1CC[C@H](C(O)=O)CC1 JROFGZPOBKIAEW-HAQNSBGRSA-N 0.000 claims 1
- 208000010643 digestive system disease Diseases 0.000 claims 1
- 229960001433 erlotinib Drugs 0.000 claims 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims 1
- 208000018685 gastrointestinal system disease Diseases 0.000 claims 1
- 208000003243 intestinal obstruction Diseases 0.000 claims 1
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 claims 1
- 229960003784 lenvatinib Drugs 0.000 claims 1
- 230000002980 postoperative effect Effects 0.000 claims 1
- 230000009885 systemic effect Effects 0.000 claims 1
- 229960005048 toceranib Drugs 0.000 claims 1
- 229960001727 tretinoin Drugs 0.000 claims 1
- 230000004663 cell proliferation Effects 0.000 abstract description 26
- 230000037361 pathway Effects 0.000 abstract description 19
- 230000005764 inhibitory process Effects 0.000 abstract description 9
- 230000004913 activation Effects 0.000 abstract description 8
- 230000002159 abnormal effect Effects 0.000 abstract description 3
- 230000032123 mast cell apoptotic process Effects 0.000 abstract description 3
- 230000019491 signal transduction Effects 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 96
- 235000011449 Rosa Nutrition 0.000 description 63
- 210000004027 cell Anatomy 0.000 description 55
- 244000060234 Gmelina philippensis Species 0.000 description 42
- 102200076881 rs121913507 Human genes 0.000 description 36
- 108010016200 Zinc Finger Protein GLI1 Proteins 0.000 description 34
- 102100035535 Zinc finger protein GLI1 Human genes 0.000 description 24
- 230000014509 gene expression Effects 0.000 description 21
- 239000000203 mixture Substances 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 13
- 229950010895 midostaurin Drugs 0.000 description 13
- 108010088665 Zinc Finger Protein Gli2 Proteins 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000003119 immunoblot Methods 0.000 description 11
- 235000002639 sodium chloride Nutrition 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 10
- 238000001262 western blot Methods 0.000 description 10
- 102000007469 Actins Human genes 0.000 description 9
- 108010085238 Actins Proteins 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 102100035558 Zinc finger protein GLI2 Human genes 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 101001074042 Homo sapiens Transcriptional activator GLI3 Proteins 0.000 description 8
- 102100035559 Transcriptional activator GLI3 Human genes 0.000 description 8
- 238000012423 maintenance Methods 0.000 description 8
- 102000003693 Hedgehog Proteins Human genes 0.000 description 7
- 108090000031 Hedgehog Proteins Proteins 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 208000032839 leukemia Diseases 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 230000008410 smoothened signaling pathway Effects 0.000 description 7
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 7
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 230000006698 induction Effects 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 230000030833 cell death Effects 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 238000010195 expression analysis Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- 208000000516 mast-cell leukemia Diseases 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 4
- 101150017888 Bcl2 gene Proteins 0.000 description 4
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 4
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- FYBHCRQFSFYWPY-UHFFFAOYSA-N purmorphamine Chemical compound C1CCCCC1N1C2=NC(OC=3C4=CC=CC=C4C=CC=3)=NC(NC=3C=CC(=CC=3)N3CCOCC3)=C2N=C1 FYBHCRQFSFYWPY-UHFFFAOYSA-N 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000011269 treatment regimen Methods 0.000 description 4
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102000012850 Patched-1 Receptor Human genes 0.000 description 3
- 108010065129 Patched-1 Receptor Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 3
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000002596 correlated effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000003762 quantitative reverse transcription PCR Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000011285 therapeutic regimen Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 102000003952 Caspase 3 Human genes 0.000 description 2
- 108090000397 Caspase 3 Proteins 0.000 description 2
- 101000606317 Drosophila melanogaster Protein patched Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000716729 Homo sapiens Kit ligand Proteins 0.000 description 2
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000009438 IgE Receptors Human genes 0.000 description 2
- 108010073816 IgE Receptors Proteins 0.000 description 2
- 201000009004 Indolent systemic mastocytosis Diseases 0.000 description 2
- 239000007760 Iscove's Modified Dulbecco's Medium Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- HVTFEHJSUSPQBK-DNJDGUCCSA-N chembl504404 Chemical compound C([C@]1(O)C(=O)O2)C[C@@H]3[C@@]4(C)C(=O)C=CCC4=CC[C@H]3[C@](O3)(OC4)C(=O)[C@@H]5[C@@]31[C@]2(C)[C@H]1C[C@]5(C)[C@@H]4C(=O)O1 HVTFEHJSUSPQBK-DNJDGUCCSA-N 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000002301 combined effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000007783 downstream signaling Effects 0.000 description 2
- 102000055151 human KITLG Human genes 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000003757 reverse transcription PCR Methods 0.000 description 2
- 102220197803 rs121913521 Human genes 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229960004449 vismodegib Drugs 0.000 description 2
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 description 2
- VSLWNSSUMFSGFF-IFSNGKJOSA-N (1R,2R,4R,6S,11R,12S,15R,18S,19R,20S,21S,23R,26S)-15-hydroxy-11,18,21-trimethyl-5,17,24,28,29-pentaoxanonacyclo[17.9.1.11,20.02,12.04,6.06,11.015,19.018,23.021,26]triacont-8-ene-10,16,25,30-tetrone Chemical compound C([C@]1(O)C(=O)O2)C[C@@H]3[C@@]4(C)C(=O)C=CC[C@@]54O[C@@H]5C[C@H]3[C@](O3)(OC4)C(=O)[C@@H]5[C@@]31[C@]2(C)[C@H]1C[C@]5(C)[C@@H]4C(=O)O1 VSLWNSSUMFSGFF-IFSNGKJOSA-N 0.000 description 1
- UXYYOHOTPOQJPD-OEPOZYLCSA-N (1r,4e,7e,11r)-3,3,7,11-tetramethyl-12-oxabicyclo[9.1.0]dodeca-4,7-dien-6-one Chemical compound C1C(C)(C)\C=C\C(=O)C(/C)=C/CC[C@@]2(C)O[C@@H]21 UXYYOHOTPOQJPD-OEPOZYLCSA-N 0.000 description 1
- WCWUXEGQKLTGDX-LLVKDONJSA-N (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@H](O)C)=C1 WCWUXEGQKLTGDX-LLVKDONJSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- POERAARDVFVDLO-QGZVFWFLSA-N 2-[5-[(2r)-4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1-yl]pyrazin-2-yl]propan-2-ol Chemical compound C([C@H]1C)N(C=2C(=C(C)C(CC=3C=CC=CC=3)=NN=2)C)CCN1C1=CN=C(C(C)(C)O)C=N1 POERAARDVFVDLO-QGZVFWFLSA-N 0.000 description 1
- USWLOKMMUTWFMD-UHFFFAOYSA-N 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine Chemical compound C1=NC=CC(C2=C(C(=C(S2)C=2C=CN=CC=2)C=2C=CN=CC=2)C=2C=CN=CC=2)=C1 USWLOKMMUTWFMD-UHFFFAOYSA-N 0.000 description 1
- ZULPZIIPOBSSNQ-UHFFFAOYSA-N 4-fluoro-n-methyl-n-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-yl]-2-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.C=1C=C(F)C=C(C(F)(F)F)C=1C(=O)N(C)C(CC1)CCN1C(C1=CC=CC=C11)=NN=C1C1=CC=NN1C ZULPZIIPOBSSNQ-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- ZADWXQMNNVICKB-UHFFFAOYSA-N 6-ethyl-n-[1-(2-hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-phenacyl-3-(2,2,2-trifluoroethoxy)pyrrolo[3,2-c]pyridine-2-carboxamide Chemical compound FC(F)(F)COC=1C=2C(=O)N(CC(=O)C=3C=CC=CC=3)C(CC)=CC=2N(C)C=1C(=O)NC1CCN(C(=O)CO)CC1 ZADWXQMNNVICKB-UHFFFAOYSA-N 0.000 description 1
- YXHLJMWYDTXDHS-IRFLANFNSA-N 7-aminoactinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=C(N)C=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 YXHLJMWYDTXDHS-IRFLANFNSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108091012583 BCL2 Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010061728 Bone lesion Diseases 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- QASFUMOKHFSJGL-LAFRSMQTSA-N Cyclopamine Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H](CC2=C3C)[C@@H]1[C@@H]2CC[C@@]13O[C@@H]2C[C@H](C)CN[C@H]2[C@H]1C QASFUMOKHFSJGL-LAFRSMQTSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 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
- 206010017076 Fracture Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 102100035960 Hedgehog-interacting protein Human genes 0.000 description 1
- 101710164669 Hedgehog-interacting protein Proteins 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 101001008874 Homo sapiens Mast/stem cell growth factor receptor Kit Proteins 0.000 description 1
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 102100025748 Mothers against decapentaplegic homolog 3 Human genes 0.000 description 1
- 101710143111 Mothers against decapentaplegic homolog 3 Proteins 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 238000002944 PCR assay Methods 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033661 Pancytopenia Diseases 0.000 description 1
- 241000051107 Paraechinus aethiopicus Species 0.000 description 1
- 102000000017 Patched Receptors Human genes 0.000 description 1
- 108010069873 Patched Receptors Proteins 0.000 description 1
- HZLFFNCLTRVYJG-WWGOJCOQSA-N Patidegib Chemical compound C([C@@]1(CC(C)=C2C3)O[C@@H]4C[C@H](C)CN[C@H]4[C@H]1C)C[C@H]2[C@H]1[C@H]3[C@@]2(C)CC[C@@H](NS(C)(=O)=O)C[C@H]2CC1 HZLFFNCLTRVYJG-WWGOJCOQSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- VSLWNSSUMFSGFF-MYAADXCVSA-N Physalin F Natural products O=C1[C@]2(O)[C@@]34[C@@](C)(O1)[C@H]1OC(=O)[C@H]5[C@@](C)([C@@H]3C(=O)[C@@](O4)(OC5)[C@H]3[C@@H]([C@@]4(C)C(=O)C=CC[C@@]54O[C@@H]5C3)CC2)C1 VSLWNSSUMFSGFF-MYAADXCVSA-N 0.000 description 1
- VSLWNSSUMFSGFF-TUIZZUNUSA-N Physalin J Natural products O=C1[C@]2(O)[C@@]34[C@@](C)(O1)[C@H]1OC(=O)[C@H]5[C@@](C)([C@@H]3C(=O)[C@@](O4)(OC5)[C@H]3[C@@H]([C@@]4(C)C(=O)C=CC[C@]54O[C@H]5C3)CC2)C1 VSLWNSSUMFSGFF-TUIZZUNUSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- 108060006706 SRC Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 208000032391 Smoldering systemic mastocytosis Diseases 0.000 description 1
- 208000032488 Systemic mastocytosis with associated hematologic neoplasm Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000033026 cell fate determination Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229940107200 chondroitin sulfates Drugs 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000011340 continuous therapy Methods 0.000 description 1
- QASFUMOKHFSJGL-UHFFFAOYSA-N cyclopamine Natural products C1C=C2CC(O)CCC2(C)C(CC2=C3C)C1C2CCC13OC2CC(C)CNC2C1C QASFUMOKHFSJGL-UHFFFAOYSA-N 0.000 description 1
- 208000024389 cytopenia Diseases 0.000 description 1
- 210000004395 cytoplasmic granule Anatomy 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- KTTMEOWBIWLMSE-UHFFFAOYSA-N diarsenic trioxide Chemical compound O1[As](O2)O[As]3O[As]1O[As]2O3 KTTMEOWBIWLMSE-UHFFFAOYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- BVTBRVFYZUCAKH-UHFFFAOYSA-L disodium selenite Chemical compound [Na+].[Na+].[O-][Se]([O-])=O BVTBRVFYZUCAKH-UHFFFAOYSA-L 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 206010019847 hepatosplenomegaly Diseases 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 102000055152 human KIT Human genes 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.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 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000011147 magnesium chloride Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- WJEOLQLKVOPQFV-UHFFFAOYSA-N masitinib Chemical group C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3SC=C(N=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 WJEOLQLKVOPQFV-UHFFFAOYSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- KLRRGBHZCJLIEL-UHFFFAOYSA-N n-[2-methyl-5-(methylaminomethyl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide Chemical compound CNCC1=CC=C(C)C(NC(=O)C=2C=CC(NC=3N=C4C=CC=CC4=C(C=4C=CC=CC=4)N=3)=CC=2)=C1 KLRRGBHZCJLIEL-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 239000012740 non-selective inhibitor Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007331 pathological accumulation Effects 0.000 description 1
- 230000009589 pathological growth Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- OHFDBBFDFZXHJQ-UHFFFAOYSA-N phenylarsane Chemical compound [AsH2]C1=CC=CC=C1 OHFDBBFDFZXHJQ-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 239000013037 reversible inhibitor Substances 0.000 description 1
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 1
- 229960000215 ruxolitinib Drugs 0.000 description 1
- 229950009919 saracatinib Drugs 0.000 description 1
- OUKYUETWWIPKQR-UHFFFAOYSA-N saracatinib Chemical compound C1CN(C)CCN1CCOC1=CC(OC2CCOCC2)=C(C(NC=2C(=CC=C3OCOC3=2)Cl)=NC=N2)C2=C1 OUKYUETWWIPKQR-UHFFFAOYSA-N 0.000 description 1
- 229960005569 saridegib Drugs 0.000 description 1
- 210000002955 secretory cell Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- PTLRDCMBXHILCL-UHFFFAOYSA-M sodium arsenite Chemical compound [Na+].[O-][As]=O PTLRDCMBXHILCL-UHFFFAOYSA-M 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000011781 sodium selenite Substances 0.000 description 1
- 229960001471 sodium selenite Drugs 0.000 description 1
- 235000015921 sodium selenite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 229960005325 sonidegib Drugs 0.000 description 1
- VZZJRYRQSPEMTK-CALCHBBNSA-N sonidegib Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(N=C1)=CC=C1NC(=O)C1=CC=CC(C=2C=CC(OC(F)(F)F)=CC=2)=C1C VZZJRYRQSPEMTK-CALCHBBNSA-N 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 206010042772 syncope Diseases 0.000 description 1
- 208000026901 systemic mastocytosis with an associated clonal hematologic non-mast cell lineage disease Diseases 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- WYTCGROMPOXACM-GMUFEBLZSA-N zerumbone epoxide Natural products O[C@H]/1/C(/C)=C\CC[C@@]2(C)O[C@@H]2CC(C)(C)/C=C\1 WYTCGROMPOXACM-GMUFEBLZSA-N 0.000 description 1
Images
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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
本発明は、肥満細胞疾患の処置のための方法及び医薬組成物に関する。
肥満細胞疾患は、ヒトの健康において特に懸念されている。例えば、肥満細胞症は、1つ以上の組織における異常な肥満細胞の病的な増殖及び蓄積によって特徴付けられる疾患である。肥満細胞症には、皮膚に限定して発症する皮膚肥満細胞症(CM)(小児により多い)及び全身性肥満細胞症(SM)という2つの病型がある。全身性肥満細胞症では、肥満細胞は、1つ以上の皮膚外組織に蓄積する。全身性肥満細胞症は肥満細胞疾患の10%を占め、全身性肥満細胞症の大半(80%)は、チロシンキナーゼ受容体KITの機能獲得型D816V突然変異を示し、幹細胞因子の活性化とは独立して、KITシグナル伝達の恒常的活性化を誘導する。この突然変異により、肥満細胞の産生は増加し、皮膚外臓器への蓄積(骨髄、リンパ節、肝臓、消化管、脾臓)が起こり、これは臓器不全をもたらし得る。残念なことに、活性化させるD816V KIT突然変異は、FDAによって認可されている全身性肥満細胞症の現在利用可能なチロシンキナーゼ阻害剤(TKI)であるイマチニブによる処置に対する耐性を伴うことが知られている。したがって、肥満細胞症の処置のための新規な効果的な治療薬は優先事項である。
本発明は、肥満細胞疾患の処置のための方法及び医薬組成物に関する。特に、本発明は特許請求の範囲によって定義される。
本発明は、治療有効量のヘッジホッグ阻害剤を患者に投与する工程を含む、それを必要とする患者における肥満細胞疾患の処置法に関する。
方法
細胞培養
様々な肥満細胞型(臍帯血CD34+細胞に由来する初代肥満細胞、ヒトMCL由来細胞株HMC−1、樹立された3つのヒト肥満細胞株ROSA−WT及びROSA−D816V、ROSA KITΔ417−419insY(Saleh R et al, A new human mast cell line expressing a functional IgE receptor converts to tumorigenic growth by KIT D816V transfection Blood 2014)、並びに肥満細胞症白血病患者の末梢血から選別された白血病肥満細胞)を使用して、肥満細胞増殖におけるヘッジホッグシグナル伝達経路の関与を示し、増殖停止及びアポトーシスに対するヘッジホッグ阻害剤の能力を実証した。ヒトMCL由来細胞株HMC−1は、フランス、パリのMichel Arock博士によって親切にも贈呈された。2つのサブクローン、すなわち、KIT V560Gを発現しているHMC−1.1、並びにKIT V560G及びKIT D816Vを発現しているHMC−1.2を使用した。
上記の各種細胞に由来する500万個の細胞を一晩かけて飢餓させた後、細胞を、様々な用量のヘッジホッグ経路の化学物質アゴニスト(例えばプルモルファミン)又はアンタゴニスト(例えばGant61)を用いて、いくつかの時間経過をかけて処置した。次いで、細胞を収集してRNA又はタンパク質を抽出し、RT−qPCR又はウェスタンブロット分析による遺伝子発現分析を実施した。ヘッジホッグ遺伝子Gli1−2−3、Smo、Patch受容体、SHH−IHH−DHHリガンド、及び腫瘍サプレッサーBcl2遺伝子を調べた。アポトーシス(Bcl2、カスパーゼ3、Bcl−xl)及びPI3K/AKT/mTOR経路に関与するタンパク質である、ヘッジホッグタンパク質(Gli1及びGli3)を調べた。
細胞増殖の動態アッセイを、IncuCyte(登録商標)生細胞分析システムを使用して10000個の細胞/ウェルで3回ずつ、1週間の間に、化合物Gant61、ビスモデギブを個々に又は組み合わせたものの存在下又は非存在下において実施して、肥満細胞増殖に対するそれらの効果を決定した。化合物を初日に様々な用量で加え、培地は7日間にわたり変更しなかった。週の終わりに、肥満細胞の死滅を、7−アミノ−アクチノマイシン生存判定染色溶液を使用してフローサイトメトリーによって調べた。
肥満細胞におけるヘッジホッグ標的遺伝子の発現
肥満細胞(MC)におけるヘッジホッグ活性を評価するために、本発明者らは、様々な肥満細胞型(初代肥満細胞株、白血病肥満細胞株、及びヒト肥満細胞株)におけるGLI1−2−3遺伝子の発現を探索した(材料及び方法を参照)。ウェスタンブロット(図1a)及びRT−qPCR(図1b)によって得られた予備調査結果は、様々な細胞型において様々な発現パターンを有するGLI1及び/又はGLI2及び/又はGLI3の発現を実証し、これにより初めて、正常な及び異常なヒト肥満細胞におけるヘッジホッグシグナル伝達経路の活性化が実証された。
肥満細胞におけるヘッジホッグ古典的経路を探索するために、本発明者らは、ヒト肥満細胞株におけるSMOアゴニストであるプルモルファミンによる刺激後に、GLI1タンパク質の発現を分析した。GLI1の発現は、プルモルファミンによる刺激後、特にROSA KIT D816Vにおいて刺激から24時間後に明瞭に増加した(図2)。これらの予備調査結果により本発明者らは、肥満細胞増殖に対する、ヘッジホッグ経路の阻害の結果、特に古典的経路の阻害の結果を探索した。
漸増量のビスモデギブ(10、20、50μM)を介したヘッジホッグシグナル伝達経路の阻害は、用量依存的にROSA細胞株の増殖を妨げた(図3)。この阻害は、ROSA KIT WT細胞株においてよりもKITの突然変異したROSA細胞株(ROSA KIT D816V及びK417)における方がより壮大であった(図3b及び3c)
図5は、KIT−D816V突然変異を有する又は有さない様々な肥満細胞系統における、GLI転写因子の発現分析を示す。
本出願全体を通して、様々な参考文献が、本発明が属する技術分野の最新技術を記載する。これらの参考文献の開示は、ここに参照することにより本開示に組み込まれる。
Claims (6)
- 治療有効量のヘッジホッグ阻害剤を患者に投与する工程を含む、それを必要とする患者における肥満細胞疾患の処置法。
- 肥満細胞疾患が、肥満細胞活性化症候群;肥満細胞症;特発性蕁麻疹;慢性蕁麻疹;アトピー性皮膚炎;特発性アナフィラキシー;IgEにより媒介される及びIgEにより媒介されないアナフィラキシー;血管浮腫;アレルギー疾患;過敏性腸症候群;肥満細胞性胃腸炎;肥満細胞性大腸炎;線維筋痛症;腎線維症;アテローム性動脈硬化症;心筋虚血;高血圧;うっ血性心不全;掻痒;慢性掻痒;慢性腎不全に続発する掻痒;肥満細胞に関連した心臓、血管、腸、脳、腎臓、肝臓、膵臓、筋肉、骨、及び皮膚の容態;CNS疾患、例えばパーキンソン病及びアルツハイマー病;代謝疾患、例えば糖尿病;鎌状赤血球症;自閉症;慢性疲労症候群;ループス;慢性ライム病;間質性膀胱炎;多発性硬化症;がん;片頭痛;乾癬;好酸球性食道炎;好酸球性胃腸炎;チャーグ・ストラウス症候群;好酸球増加症候群;好酸球性筋膜炎;好酸球性胃腸障害;慢性特発性蕁麻疹;心筋炎;ヒルシュスプルング病関連腸炎;術後腸閉塞;創傷治癒;脳卒中;一過性脳虚血発作;疼痛;神経痛;末梢神経障害;急性冠動脈症候群;膵炎;皮膚筋炎;線維性皮膚疾患;がん関連疼痛;潰瘍性大腸炎;炎症性腸疾患;放射線性腸炎;セリアック病;グルテン性腸症;放射線性膀胱炎;膀胱痛症候群;肝炎;肝線維症;肝硬変;関節リウマチ;全身エリテマトーデス;及び血管炎からなる群より選択される、請求項1の方法。
- 肥満細胞疾患が、皮膚肥満細胞症;全身性肥満細胞症;及び全身性無痛性肥満細胞症からなる群より選択される、請求項1の方法。
- 肥満細胞症の発病が、特にKITの突然変異が原因である、チロシンキナーゼ受容体KITの恒常的活性化に起因する、請求項2の方法。
- ヘッジホッグ阻害剤が、ビスモデギブ又はGANT61である、請求項1の方法。
- ヘッジホッグ阻害剤が、PKC412(ミドスタウリン)、アファチニブ、アリトレチノイン、アキシチニブ、バフェチニブ、ベキサロテン、BI−2536、ボスチニブ、ブリバニブ、カネルチニブ、セディラニブ、CP724714、クリゾチニブ、ダサチニブ、ダヌセルチブ、ドビチニブ、E7080、エルロチニブ、エベロリムス、フォスタマチニブ、ゲフィチニブ、イマチニブ、ラパチニブ、レスタウルチニブ、リンシチニブ、マシチニブ、モテサニブ、ネラチニブ、ニロチニブ、NVP TAE−684、OSI−027、OSI−420、OSI−930、パゾパニブ、ペリチニブ、PF573228、レゴラフェニブ、ロミデプシン、ルキソリチニブ、サラカチニブ、ソラフェニブ、スニチニブ、TAE226、TAE684、タンデュチニブ、テラチニブ、タウチニブ、テムシロリムス、トセラニブ、トファシチニブ、トザセルチブ、トレチノイン、バンデタニブ、バタラニブ、ベムラフェニブ、ボリノスタット、及びWZ4002などのチロシンキナーゼ阻害剤と組み合わせて患者に投与される、請求項1の方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2022205739A JP2023030112A (ja) | 2017-05-18 | 2022-12-22 | 肥満細胞疾患の処置のための方法及び医薬組成物 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP17305573 | 2017-05-18 | ||
EP17305573.2 | 2017-05-18 | ||
PCT/EP2018/062889 WO2018211007A1 (en) | 2017-05-18 | 2018-05-17 | Methods and pharmaceutical compositions for the treatment of mast cell diseases |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022205739A Division JP2023030112A (ja) | 2017-05-18 | 2022-12-22 | 肥満細胞疾患の処置のための方法及び医薬組成物 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2020519581A true JP2020519581A (ja) | 2020-07-02 |
JP7323457B2 JP7323457B2 (ja) | 2023-08-08 |
Family
ID=58779045
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019561135A Active JP7323457B2 (ja) | 2017-05-18 | 2018-05-17 | 肥満細胞疾患の処置のための方法及び医薬組成物 |
JP2022205739A Pending JP2023030112A (ja) | 2017-05-18 | 2022-12-22 | 肥満細胞疾患の処置のための方法及び医薬組成物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2022205739A Pending JP2023030112A (ja) | 2017-05-18 | 2022-12-22 | 肥満細胞疾患の処置のための方法及び医薬組成物 |
Country Status (4)
Country | Link |
---|---|
US (1) | US11389434B2 (ja) |
EP (1) | EP3624798A1 (ja) |
JP (2) | JP7323457B2 (ja) |
WO (1) | WO2018211007A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112741904B (zh) * | 2019-10-29 | 2023-03-21 | 中国科学院分子细胞科学卓越创新中心 | Hedgehog信号通路抑制剂治疗自闭症的用途 |
Family Cites Families (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5618829A (en) | 1993-01-28 | 1997-04-08 | Mitsubishi Chemical Corporation | Tyrosine kinase inhibitors and benzoylacrylamide derivatives |
KR960703622A (ko) | 1993-07-15 | 1996-08-31 | 수잔 포오덴 | 단백질 티로신 키나아제 억제제의 프로드러그(prodrugs of protein tyrosine kinase inhibitors) |
US5804396A (en) | 1994-10-12 | 1998-09-08 | Sugen, Inc. | Assay for agents active in proliferative disorders |
US5639757A (en) | 1995-05-23 | 1997-06-17 | Pfizer Inc. | 4-aminopyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors |
EP0892789B2 (en) | 1996-04-12 | 2009-11-18 | Warner-Lambert Company LLC | Irreversible inhibitors of tyrosine kinases |
ZA986732B (en) | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitiors of tyrosine kinases |
US6100254A (en) | 1997-10-10 | 2000-08-08 | Board Of Regents, The University Of Texas System | Inhibitors of protein tyrosine kinases |
US6740665B1 (en) | 1999-02-10 | 2004-05-25 | Ramachandran Murali | Tyrosine kinase inhibitors and methods of using the same |
US6245759B1 (en) | 1999-03-11 | 2001-06-12 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
JP2003503354A (ja) | 1999-06-30 | 2003-01-28 | メルク エンド カムパニー インコーポレーテッド | Srcキナーゼ阻害剤化合物 |
US6329380B1 (en) | 1999-06-30 | 2001-12-11 | Merck & Co., Inc. | SRC kinase inhibitor compounds |
CA2383546A1 (en) | 1999-06-30 | 2001-01-04 | William H. Parsons | Src kinase inhibitor compounds |
KR20020027635A (ko) | 1999-09-10 | 2002-04-13 | 폴락 돈나 엘. | 티로신 키나제 억제제 |
DE60017179T2 (de) | 1999-10-19 | 2006-01-05 | Merck & Co., Inc. | Tyrosin kinaseinhibitoren |
JP2003512353A (ja) | 1999-10-19 | 2003-04-02 | メルク エンド カムパニー インコーポレーテッド | チロシンキナーゼ阻害剤 |
US6794393B1 (en) | 1999-10-19 | 2004-09-21 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
US6313138B1 (en) | 2000-02-25 | 2001-11-06 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
US6420382B2 (en) | 2000-02-25 | 2002-07-16 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
ES2255621T3 (es) | 2001-06-22 | 2006-07-01 | MERCK & CO., INC. | Inhibidores de tirosina quinasa. |
BR0211513A (pt) | 2001-07-27 | 2005-08-30 | Curis Inc | Mediadores de caminhos sinalizantes de hedgehog, composições e usos relacionados ao mesmo |
WO2003011836A1 (en) | 2001-08-01 | 2003-02-13 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
WO2003020276A1 (en) | 2001-08-30 | 2003-03-13 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
EP2404602A1 (en) | 2005-08-22 | 2012-01-11 | The Johns Hopkins University | Hedgehog pathway antagonists to treat cancer |
WO2007109571A2 (en) | 2006-03-17 | 2007-09-27 | Prometheus Laboratories, Inc. | Methods of predicting and monitoring tyrosine kinase inhibitor therapy |
ES2569941T3 (es) * | 2007-06-07 | 2016-05-13 | Novartis Ag | Derivados de bifenilcarboxamida como moduladores de la ruta de hedgehog |
EP2187967B1 (en) * | 2007-08-16 | 2013-04-24 | Irm Llc | Methods and compositions for treating cancers |
FR2930552B1 (fr) | 2008-04-24 | 2012-10-12 | Centre Nat Rech Scient | N-acylthiourees et n-acylurees inhibiteurs de la voie de signalisation des proteines hedgehog |
US8778927B2 (en) * | 2008-10-01 | 2014-07-15 | Novartis Ag | Smoothened antagonism for the treatment of hedgehog pathway-related disorders |
AR077014A1 (es) | 2009-06-19 | 2011-07-27 | Lilly Co Eli | Compuesto derivado de ftalazina 1,4-disustituida, composicion farmaceutica que lo comprende y uso para preparar un medicamento util para el tratamiento de cancer |
US20140147415A1 (en) | 2010-11-05 | 2014-05-29 | Ab Science | Treatment of mastocytosis with masitinib |
EP2806948B1 (en) * | 2012-01-27 | 2020-01-15 | New York University | Method for enhancing remyelination using gli1 inhibitors |
US20150225476A1 (en) * | 2012-09-21 | 2015-08-13 | Agency For Science, Technology And Research | Method for treating a disease or disorder of the lung by inhibition of the hedgehog pathway |
US9192609B2 (en) | 2013-04-17 | 2015-11-24 | Hedgepath Pharmaceuticals, Inc. | Treatment and prognostic monitoring of proliferation disorders using hedgehog pathway inhibitors |
GB201309508D0 (en) | 2013-05-28 | 2013-07-10 | Redx Pharma Ltd | Compounds |
WO2017060308A1 (en) | 2015-10-05 | 2017-04-13 | Ab Science | Treatment of severe systemic mastocytosis with masitinib |
-
2018
- 2018-05-17 JP JP2019561135A patent/JP7323457B2/ja active Active
- 2018-05-17 US US16/614,595 patent/US11389434B2/en active Active
- 2018-05-17 WO PCT/EP2018/062889 patent/WO2018211007A1/en unknown
- 2018-05-17 EP EP18724562.6A patent/EP3624798A1/en active Pending
-
2022
- 2022-12-22 JP JP2022205739A patent/JP2023030112A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
WO2018211007A1 (en) | 2018-11-22 |
JP7323457B2 (ja) | 2023-08-08 |
JP2023030112A (ja) | 2023-03-07 |
US11389434B2 (en) | 2022-07-19 |
EP3624798A1 (en) | 2020-03-25 |
US20200108053A1 (en) | 2020-04-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230146638A1 (en) | Treatment of EGFR-Driven Cancer with Fewer Side Effects | |
EP3515446B1 (en) | Therapeutic combinations comprising a raf inhibitor and a erk inhibitor | |
TWI680760B (zh) | 治療黑色素瘤的藥物組合 | |
Chen et al. | Clinical perspective of afatinib in non-small cell lung cancer | |
JP6911019B2 (ja) | Egfr−tki耐性を獲得した肺癌の治療薬 | |
JP2021512101A (ja) | 肥満細胞症の治療のための併用療法 | |
US11395821B2 (en) | Treatment of EGFR-driven cancer with fewer side effects | |
JP2023145467A (ja) | 組み合わせ療法 | |
TW201639578A (zh) | 阿吡莫德之活性代謝物及其用途 | |
CN109069461A (zh) | 与髓源性抑制细胞相关的病症的治疗方法 | |
TW201244716A (en) | Combination of a phosphatidylinositol-3-kinase (PI3K) inhibitor and a mTOR inhibitor | |
SG194047A1 (en) | Combinations of akt and mek inhibitor compounds, and methods of use | |
WO2018235103A1 (en) | METHOD OF TREATING CANCER | |
WO2023114984A1 (en) | Tead inhibitors and uses thereof | |
Wen et al. | Medulloblastoma drugs in development: Current leads, trials and drawbacks | |
EP2968564B1 (en) | Combinations of inhibitors of mek, egfr and erbb2 in the treatment of kras-mutant lung cancer | |
JP2023030112A (ja) | 肥満細胞疾患の処置のための方法及び医薬組成物 | |
WO2018064851A1 (zh) | 低剂量西地那非作为抗肿瘤药物的应用 | |
EP3858836A1 (en) | Compound and use thereof | |
CA2479495A1 (en) | Remedy for glioblastoma | |
US20210308106A1 (en) | Methods and pharmaceutical compositions for the treatment of systemic mastocytosis | |
JP2016520662A (ja) | Pi3k阻害剤および微小管不安定化剤の医薬組み合わせ | |
US10196378B2 (en) | Inhibitors of BCR-ABL mutants and use thereof | |
CN113453671A (zh) | 用于治疗癌症的Raf抑制剂和CDK4/6抑制剂的组合疗法 | |
US11957677B2 (en) | Cancer treatment using FGFR inhibitors and PLK1 inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210217 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A712 Effective date: 20211213 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220308 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220607 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20220823 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20221222 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20221222 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20230110 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20230117 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20230307 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230605 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20230627 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230727 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7323457 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |