LOXO-101 1223403-58-4
Latar mburi
IC50: kisaran nanomolar sing kurang kanggo nyegah kabeh anggota kulawarga TRK
LOXO-101 minangka hambat reseptor kinase tropomyosin (TRK).
Kulawarga TRK reseptor neurotrofin lan ligan neurotrofin ngatur tuwuhing neuron, diferensiasi lan kaslametan.
In vitro: Ing panaliten sadurunge, LOXO-101 dievaluasi kanggo hambatan enzim kinase target target tumrap panel kinase non-TRK kanthi konsentrasi 1.000 nM lan ATP konsentrasi ing sekitar Km. Asil nuduhake manawa LOXO-101 duwe hambatan luwih saka 50% kanggo mung siji non-TRK kinase, yaiku TNK2 kanthi IC50 576 nM. Kajaba iku, ora ana hambatan hERG sing relevan utawa uga pengamatan QT sing dawa [1].
In vivo: Penelitian kewan nemokake yen LOXO-101 bisa nyegah pertumbuhan tumor vivo. Tikus mudo Athymic sing disuntik karo sel KM12 ditambani kanthi oral kanthi LOXO-101 saben dina suwene 2 minggu, lan hambatan tumor gumantung dosis diamati, nuduhake kemampuan LOXO-101 kanggo nyegah tuwuhing tumor in-vivo [1].
Uji klinis: Tahap multicenter sinau dosis-eskalasi ing pasien kanthi tumor solid maju (ClinicalTrials.gov no. NCT02122913) ditindakake ing 2014 kanggo ngevaluasi keamanan lan PK LOXO-101. Pasien dosis kaping pindho utawa kaping pindho saben dinane sajrone 28 dina dosis terus-terusan nambah kohort. Data awal PK lan keamanan nuduhake manawa tingkat plasma gratis LOXO-101 ana ing konsentrasi sing ana gandhengane karo biologis kanggo nyegah onkogen TRK. Ing panliten iki, pasien sing pertama lan siji nuduhake fusi TRK lan regresi tumor klinis sing cepet sing katon kanthi perawatan LOXO-101 [1].
Referensi:
[1] Doebele RC dkk. Fusion NTRK Onkogenik ing Pasien sing Sarcoma Tisu Lunak kanthi Tanggepan Pambebas Kinase Sing Gegandhengan Tropomyosin LOXO-101 Discov Kanker. 2015 Okt; 5 (10): 1049-57.
Katrangan
Larotrectinib (LOXO-101) minangka penghambat selektif oral ATP kanthi reseptor reseptor kulawarga kinase (TRK) sing gegandhengan tropomyosin, kanthi konsentrasi hambat nanomolar 50% tumrap kabeh telung isoform (TRKA, B, lan C).
Nyoba Klinis
Nomer NCT | Sponsor | Kahanan | Tanggal Mulai |
Tahap |
NCT03025360 | Bayer | Tumor Harbour Fusion NTRK |
|
|
NCT02637687 | Bayer | Tumor Padat Harbour Fusion NTRK | 16 Desember 2015 |
Fase 1 | Fase 2 |
NCT02122913 | Bayer | Tumor Padat Harbour Fusion NTRK | 4 Mei 2014 |
Tahap 1 |
NCT03213704 | Institut Kanker Nasional (NCI) | Neoplasma Solid Malignant Lanjut | Ependymoma Ulangan | Balung Ewing Sarcoma + Tumor Neuroektodermal Primitif Periferal | Glioma Balen | Hepatoblastoma Ambalan | Balen Sel Langerhans Histiocytosis | Balung Sel Kronus Malignan | Gendhung Malignen Resuren | Lymphoma Non-Hodgkin | Osteosarcoma ambalan | Tumor Rhabdoid ambalan | Rhabdomyosarcoma ambalan | Sarcoma jaringan lunak ambalan | Ependymoma refraktori | Refractory Ewing Sarcoma + Peripheral Primitive Neuroectodermal Tumor | Refractory Grioma Refractory Malignant Glioma | Refractory Malignant Solid Neoplasm | Refractory Neuroblastoma | Refractory Non-Hodgkin Lymphoma | Refractory Osteosarcoma | Refractory Central Nervous System Neoplasma | Refractory Tumor Rhabdoid | Refractory Rhabdomyosarcoma | Wilms Tumor | 24 Juli 2017 |
Tahap 2 |
NCT02465060 | Institut Kanker Nasional (NCI) | Neoplasma Solid ganas maju | Karsinoma kandung kemih | Karsinoma Payudara | Karsinoma serviks | Karsinoma Kolonial | Neoplasma Rahim Malignan | Melanoma | Karsinoma Ovarium | Karsinoma Pankreas | Plasma Cell Myeloma | Karsinoma Prostat | Karsinoma Rektal | Karsinoma Kandung Kambuh | Karsinoma Payudara Kambuh | Karsinoma serviks Kronik Kanker | Glioma Kambuh | Karsinoma Kepala lan Gulu Kambuh | Karsinoma Ati Kambuh | Karsinoma Paru-paru Kambuh | Limfoma Kambuh | Neoplasma Malignan Kambuh | Melanoma Kambuh | Karsinoma Ovarium Kambuh | Karsinoma Pankreas Kambuh | Kanker Sel Plasma Kambuh Karsinoma Kulit Balen | Kelenjar Tiroid Balen Karsinoma | Kanker Corpus Rahim Kambuh | Lymphoma Refractory | Neoplasma Malignan Refractory | Myeloma Plasma Refractory | Karsinoma Kulit | Karsinoma Kelenjar Tiroid | Kanker Corpus Rahim | 12 Agustus 2015 |
Tahap 2 |
NCT03834961 | Klompok Onkologi Anak | Institut Kanker Nasional (NCI) | Neoplasma Sistem saraf pusat | Fibrosarcoma Bayi | Leukemia Akut Berulang | Leukemia Akut Refraktori | Neoplasma Padat | 18 September 2019 |
Tahap 2 |
NCT04142437 | Bayer | Tumor Padat Lokal utawa Metastatik Lokal sing Nggabungake Fusion NTRK | 3 April 2020 |
|
NCT03155620 | Institut Kanker Nasional (NCI) | Neoplasma Solid Malignant Advanced | Ann Arbor Stage III Non-Hodgkin Lymphoma | Ann Arbor Stage IV Non-Hodgkin Lymphoma | Histiocytic Sarcoma | Juvenile Xanthogranuloma | Langerhans Cell Histiocytosis | Malignant Glioma | Rhabdomyosarcoma Recurrent | Epidum Akurus Hepatoblastoma ambalan | Histiocytosis Sel Langerhans Balen | Tumor Sel Kuman Malignan | Neoplasma Malignan Malignan | Medulloblastoma Ulangan | Neuroblastoma Ulangan | Limfoma Non-Hodgkin Umur | Osteosarcoma Neuropaid Neurosis | Sarcoma Tisu Lunak Kambuh | Refractory Ewing Sarcoma | Refractory Glioma | Hepatoblastoma Refractory | Langerhans Cell Histiocytosis Refractory Tumor Neuroektodermal Primitif Periferal Periferal | Neoplasma Sistem saraf primer Refractory | Tumor Rhabdoid Refraktori | Tumor Rhabdoid | Panggung III Osteosarcoma AJCC v7 | Tahap III Tisu Lemes Sarcoma AJCC v7 | Tahap IV Osteosarom | Panggung IVA Osteosarcoma AJCC v7 | Tahap IVB Osteosarcoma AJCC v7 | Wilms Tumor | 24 Juli 2017 |
Tahap 2 |
Struktur kimia
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