LOXO-101 1223403-58-4
Tom Qab
IC50: nanomolar qis ntau yam rau kev tsis sib haum xeeb ntawm txhua tus tswv cuab hauv TRK tsev neeg
LOXO-101 yog tropomyosin receptor kinases (TRK) inhibitor.
TRK tsev neeg ntawm cov neurotrophin receptors thiab lawv cov neurotrophin ligands tswj kev neuron kev loj hlob, kev sib txawv thiab kev ciaj sia.
Hauv vitro: Hauv kev tshawb nrhiav dhau los, LOXO-101 tau raug soj ntsuam rau tua-kinase enzyme inhibition tiv thaiv cov vaj huam sib luag ntawm cov tsis-TRK kinases ntawm qhov ntau ntawm 1,000 nM thiab ATP ntau nyob ib ncig ntawm Km. Cov txiaj ntsig tau pom tias LOXO-101 muaj ntau dua 50% kev txwv rau tsuas yog ib tus tsis-TRK kinase, uas yog TNK2 nrog IC50 ntawm 576 nM. Ntxiv mus, muaj tsis yog tus twg cuam tshuam hERG kev txwv tsis pub ntev QT tshuaj xyuas [1].
Hauv vivo: Kev tshawb nrhiav tsiaj pom tias LOXO-101 tau tuaj yeem tiv thaiv qhov vivo hlav loj. Cov neeg ntaus kis las nas liab kis nrog KM12 cov hlwb tau kho qhov ncauj LOXO-101 txhua hnub rau 2 lub lis piam, thiab qhov tshuaj tiv thaiv qog noj tshuaj tiv thaiv kab mob tau pom, qhia tias muaj peev xwm ntawm LOXO-101 txhawm rau inhibit hauv-vivo hlav hlav [1].
Cov chaw sim tshuaj: ntau lub sijhawm ntau ntawm kev tshawb nrhiav qhov tshuaj tiv thaiv kab mob hauv cov neeg mob uas muaj cov qog ua haujlwm nyuaj (ClinicalTrials.gov no. NCT02122913) tau ua xyoo 2014 los ntsuas kev nyab xeeb thiab PK ntawm LOXO-101. Cov neeg mob tau hno ib zaug lossis ob zaug ib hnub rau 28 hnub ntawm kev noj tshuaj ntau ntxiv hauv cov pab pawg ntxiv. Cov ntaub ntawv ua ntej PK thiab cov ntaub ntawv kev nyab xeeb qhia tias cov ntshav plasma tsis pub dawb ntawm LOXO-101 nyob ntawm qhov muaj sia txog xyoob ntoo kom thiaj li tso tseg TRK oncogenes. Hauv txoj kev tshawb nrhiav no, thawj zaug thiab tsuas yog tus neeg mob pom tias TRK fusion thiab cov kab mob qog sai sai tau pom nrog kev kho LOXO-101 [1].
Siv:
[1] Doebele RC li al. Ib qho Oncogenic NTRK Fusion hauv Tus Neeg Mob nrog Mos Cov nqaij mos Sarcoma nrog Lus Teb rau Tropomyosin-Hais txog Kinase Tus Txwv LOXO-101. Cancer Discov.2015 Lub Kaum Hli; 5 (10): 1049-57.
Kev piav qhia
Larotrectinib (LOXO-101) yog ATP-sib tw ntawm qhov ncauj, xaiv cov tshuaj tiv thaiv ntawm tropomyosin-cuam tshuam kinase (TRK) cov tsev neeg txais, nrog nanomolar qis 50% inhibitory cov tshuaj tiv thaiv txhua yam peb isoforms (TRKA, B, thiab C).
Cov Chaw Kho Mob Ntsuam Xyuas
NCT Nab Npawb | Tus tswj | Mob | Hnub Pib |
Phase |
NCT03025360 | Bayer | Tumors Harboring NTRK Fusion |
|
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NCT02637687 | Bayer | Khoom Tumors Harboring NTRK Fusion | Lub 12 hlis tim 16, 2015 |
Theem 1 | Theem 2 |
NCT02122913 | Bayer | Khoom Tumors Harboring NTRK Fusion | Tsib Hlis 4, 2014 |
Theem 1 |
NCT03213704 | Koom Haum Cancer ntawm Tebchaws (NCI) | Mob Siab Tshaj Plaws Vim Raug Mob Neurum Qhov Ntshai Ib Zaug | Cov Kev Mob Hlawv Rov Qab Los | Cov Kev Ntsuam Xyuas Neeg Lub Hlwb | Cov leeg ua hauj lwm | Cov leeg ua hauj lwm | Cov leeg muaj mob | Cov hlab ntsha Ua kom rov muaj mob | Tsis yog-Hodgkin Lymphoma | Cov Kev Txheeb Ze Osteosarcoma | Cov Kev Ntsuas Rov Qab Rhabdoid Tumour | Cov Kev Mob Rov Ntsig | Cov Khoom Siv Teeb Meem Refractory Glioma Refractory Tawv Nrho | Refractory Glioma | Malignant Glioma | Refractory Malignant Khoom Neoplasm | Refractory Neuroblastoma | Refractory Tsis-Hodgkin Lymphoma | Refractory Osteosarcoma | Refractory Lub Tsev Nruab Nrab Nruab Nrab System Neoplasm | Refractory Rhabdoid Tumor | Refractory Rhabdomyosarcoma | Wilms Tumor | Lub Xya hli ntuj 24, 2017 |
Theem 2 |
NCT02465060 | Koom Haum Cancer ntawm Tebchaws (NCI) | Advanced Malignant Khoom Neoplasm | Tsoos Carcinoma | Mob Cancer Carcinoma | Khees Xaws Carcinoma | Mob Caj Qaum Carcinoma | Ntxig Mob Carcinoma | Endometrial Carcinoma | Esophageal Carcinoma | Gastric Carcinoma | Glioma | Lub taub hau thiab caj dab Carcinoma | Mob raum Carcinoma | | Malterant Uterine Neoplasm | Melanoma | Ovarian Carcinoma | Pancreatic Carcinoma | Plasma Cell Myeloma | Prostate Carcinoma | Rhais sab Carcinoma | Kev mob plab zais zis Carcinoma | Lub sijhawm mis rov qab Carcinoma | Cov kev mob rov qab los ntawm lub ncauj tsev menyuam Carcinoma | | Cov Kev Rov Ciav Rov Qab Lub Ntshav Rov Qab Txiag | Lub taub hau thiab caj dab Carcinoma | Lub siab mob ntsws Carcinoma | Cov Kev Mob Hlawv Rov Qab Los | Ntshav Rov Qab Cum | Ntshav Rov Qab Cum | Rov Qab Zawv Zawv Daim tawv nqaij Carcinoma | Rov Qab Zawv Zawv Zawv Zawv Carcinoma | Cov Kev Ntshav Rov Qab Uterine Corpus Cancer | Lub Pob Txha Los Ntawm Lub Pob Txha Refractory Lymphoma | Refractory Malignant Khoom Neoplasm | Refractory Plawv Cell Myeloma | | Lub Yim Hli 12, 2015 |
Theem 2 |
NCT03834961 | Cov Menyuam Txoj Kev Oncology Pab Pawg | Cancer Lub Tebchaws (NCI) | Lub Hauv Paus Mob Ntshav Neoplasm | Cov Me Nyuam Hlwb Fibrosarcoma | Cov Kev Mob Ntshav Rov Qab Los Hlav | Ntsiav Tshuaj Mob Ntshav | Lub Cuaj Hli 18, 2019 |
Theem 2 |
NCT04142437 | Bayer | Hauv zos Advanced lossis Metastatic Solid Tumor Harboring ib qho NTRK Gene Fusion | Lub Plaub Hlis 3, 2020 |
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NCT03155620 | Koom Haum Cancer ntawm Tebchaws (NCI) | Advanced Malignant Cov Khoom Neoplasm | Ann Arbor Stage III Tsis-Hodgkin Lymphoma | Ann Arbor Theem IV Tsis-Hodgkin Lymphoma | Qhov Mob Hluav Taws Xob | Sarcoma | Juvenile Xanthogranuloma | Langerhans Cell keeb kwm mob hlwb | Malignant Glioma | Cov Kev Ntsuas Hluav Taws Xob | Kev Rov Ntsuas | Cov Kev Ntsuas Rov Qab Hnyav Ntsiag to | Cov Kev Mob Hliav Rov Ntsuas Lub Ntshav Rov Qab | Cov Kev Mob Hauv Tsev Lub Tsev Ib Sijhawm Txhua Hnub | Cov Kev Sib Nraum Los Tsev Mob Lub Hauv Paus | | Cov teeb meem mos ua kom zoo nkauj Sarcoma | Refractory Ewing Sarcoma | Refractory Glioma | Refractory Hepatoblastoma | Refractory Langerhans Cell Histiocytosis | Refractory Malignant Cell Cell Tumor | Refractory Malignant Lub Cell Mob Lub Pob Txha | Refractory Malignant Khoom Neoplasm | Refractory Hepatoblastoma | Refractory Neuroblastoma | Refractory Neuroblastoma Ctory Peripheral Primitive Neuroectodermal Tumor | Refractory Primary Central Nervous System Neoplasm | Refractory Rhabdoid Tumor | Refractory Rhabdomyosarcoma | Rhabdoid Tumor | Theem III Osteosarcoma AJCC v7 | Theem III Mos mos Cov nqaij Sarcoma AJCC v7 | Stage O Lub Cev Hlua V AJCC v7 | Stage O Mososi AJCC v7 | | | Stage IVA Osteosarcoma AJCC v7 | Theem IVB Osteosarcoma AJCC v7 | Wilms Tumor | Lub Xya hli ntuj 24, 2017 |
Theem 2 |
Tshuaj qauv
Kev Tawm Tsam 18 Cov Kev Ntsuas Xyuas Kom Zoo Kom Zoo Li Qub uas tau pom zoo 4, thiab 6 tej yaam num yog nyob rau hauv kev pom zoo.
Advanced thoob ntiaj teb zoo tswj system tau tso paus ruaj khov rau kev muag khoom.
Kev saib xyuas kev ua tau zoo khiav thoob plaws lub neej tag nrho ntawm cov khoom kom ntseeg tau tias qhov zoo thiab ua kom zoo.
Pawg kws tshaj lij ntxawg koom tes txhawb nqa qhov kev xav tau zoo thaum thov thiab sau npe.