Luchd-saothrachaidh agus solaraichean Sìona LOXO-101 1223403-58-4

LOXO-101 1223403-58-4

Tuairisgeul Goirid:

Ainm API	Comharradh	Ùr-ghnàthaiche	Ceann-latha crìochnachaidh patent (Na SA)
LOXO-101 1223403-58-4	Droga oncology	Oncology Loxo	Oct.21,2029

Cuir post-d thugainn

Mion-fhiosrachadh toraidh

Tagaichean toraidh

FIOSRACHADH PRODUCT

Cùl-fhiosrachadh

IC50: raon nanomolar ìosal airson casg a chuir air gach ball den teaghlach TRK

Tha LOXO-101 na inhibitor kinases receptor tropomyosin (TRK).

Bidh an teaghlach TRK de gabhadairean neurotrophin agus na ligandan neurotrophin aca a ’riaghladh fàs, eadar-dhealachadh agus mairsinn neuron.

In vitro: Ann an sgrùdadh roimhe, chaidh LOXO-101 a mheasadh airson in-bhacadh enzyme kinase far-targaid an aghaidh pannal de chinases neo-TRK aig dùmhlachd de 1,000 nM agus dùmhlachd ATP timcheall air an Km. Sheall toraidhean gu robh barrachd air 50% de bhacadh aig LOXO-101 airson dìreach aon kinase neo-TRK, a bha TNK2 le IC50 de 576 nM. A bharrachd air an sin, cha robh casg HERG buntainneach no amharc QT fada [1].

In vivo: Lorg sgrùdadh bheathaichean gu robh e comasach dha LOXO-101 bacadh a chur air fàs tumhair in vivo. Chaidh luchagan nude ath-bheòthail a chaidh an stealladh le ceallan KM12 a làimhseachadh gu beòil le LOXO-101 gach latha airson 2 sheachdain, agus chaidh casg tumhair a bha an urra ri dòs a choimhead, a ’nochdadh comas LOXO-101 gus casg a chuir air fàs tumhair in-vivo [1].

Deuchainn clionaigeach: Chaidh sgrùdadh dòs-àrdachadh ìre I multicenter ann an euslaintich le tumors cruaidh adhartach (ClinicalTrials.gov no. NCT02122913) a dhèanamh ann an 2014 gus sàbhailteachd agus PK de LOXO-101 a mheasadh. Tha euslaintich air an dòrtadh uair no dhà san latha airson 28 latha de dòsan leantainneach ann an co-thursan a tha a ’sìor fhàs. Tha dàta tòiseachaidh PK agus sàbhailteachd a ’nochdadh gu bheil na h-ìrean plasma an-asgaidh de LOXO-101 aig co-chruinneachaidhean buntainneach bith-eòlasach gus casg a chuir air oncogenes TRK. Anns an sgrùdadh seo, sheall a ’chiad agus an aon euslainteach fusion TRK agus an toirt air ais tumhair clionaigeach luath a chaidh fhaicinn le làimhseachadh LOXO-101 [1].

Fiosrachadh:
[1] Doebele RC et al. Fusion Oncogenic NTRK ann an euslaintich le Sarcoma fìnealta bog le freagairt don neach-dìon Kinase co-cheangailte ri tropomyosin LOXO-101. Cancer Discov.2015 Dàmhair; 5 (10): 1049-57.

Tuairisgeul

Tha Larotrectinib (LOXO-101) na inhibitor beòil farpaiseach ATP-farpaiseach de na gabhadairean teaghlaich kinase (TRK) tropomyosin, le dùmhlachd bacaidh 50% nanomolar ìosal an aghaidh nan trì isofoirmean (TRKA, B, agus C).

Deuchainn clionaigeach

Àireamh NCT	Urrasachd	Suidheachadh	Ceann-latha tòiseachaidh	Ìre
NCT03025360	Bayer	Tumors A ’caladh NTRK Fusion
NCT02637687	Bayer	Tumors soladach a ’caladh NTRK Fusion	16 Dùbhlachd 2015	Ìre 1 \| Ìre 2
NCT02122913	Bayer	Tumors soladach a ’caladh NTRK Fusion	4 Cèitean, 2014	Ìre 1
NCT03213704	Institiud Nàiseanta Ailse (NCI)	Neoplasm Solid Malignant adhartach \| Ependymoma ath-chuairteach \| Sarcoma Ewing ath-chuairteach + Tumor Neuroectodermal Primitive Peripheral \| Glioma Ath-chuairteach \| Hepatoblastoma Ath-chuairteach \| Langerhans Cell Histiocytosis \| Ath-chuairteachadh Malignant Germ Cell Tumor \| Ath-chuairteachadh Ath-chuairteach \| Lymphoma neo-Hodgkin \| Osteosarcoma ath-chuairteach \| Tumor Rhabdoid ath-chuairteach \| Rhabdomyosarcoma ath-chuairteach \| Sarcoma fìne bog bog ath-chuairteach \| Sarcoma Ewing teasfhulangach + Tumor Ewing teasfhulangach Glioma malignant \| Neoplasm Solid Malignant Refractory \| Neuroblastoma teasfhulangach \| lymphoma neo-Hodgkin teasfhulangach	24 Iuchar 2017	Ìre 2
NCT02465060	Institiud Nàiseanta Ailse (NCI)	Neoplasm Solid Malignant adhartach \| Carcinoma bladder \| Carcinoma broilleach \| Carcinoma ceirbheacsach \| carcinoma carcinoma \| carcinoma colorectal \| carcinoma endometrial \| carcinoma esophageal \| carcinoma gastric \| glioma \| Carcinoma ceann agus amhach \| Carcinoma dubhaig \| carcinoma cnàmhan dubhaig \| \| Neoplasm uterine malignant \| Melanoma \| Carcinoma ovarian \| Carcinoma pancreatic \| Myeloma cealla plasma \| Carcinoma próstatach \| carcinoma carcinoma \| Carcinoma bladder ath-chuairteach \| Carcinoma broilleach ath-chuairteach \| Carcinoma ceirbheacsach ath-chuairteach \| Carcinoma colur ath-chuairteach \| \| Glioma ath-chuairteach \| Carcinoma ceann ath-chuairteach agus amhach \| Carcinoma grùthan ath-chuairteach \| Carcinoma sgamhain ath-chuairteach \| lymphoma ath-chuairteach \| Neoplasm so-leònte ath-chuairteach \| Melanoma ath-chuairteach \| Carcinoma Ovarian Ath-chuairteach \| Carcinoma Pancreatic Ath-chuairteach \| Carcinoma Ath-chuairteach \| Carcinoma craiceann ath-chuairteach \| Gland thyroid ath-chuairteach Carcinoma \| Ailse Corpus Uterine Ath-chuairteach \| Lymphoma teasfhulangach \| Neoplasm so-fhaicsinneach mì-shoilleir \| Myeloma cealla plasma teasfhulangach \| carcinoma craiceann \| Carcinoma gland thyroid \| aillse corp uterine	12 Lùnastal, 2015	Ìre 2
NCT03834961	Buidheann Oncology na Cloinne \| Institiud Nàiseanta Ailse (NCI)	Neoplasm an t-Siostam Nervous Central \| Fibrosarcoma leanaban \| Leucemia géar ath-chuairteach \| leucemia géar teasfhulangach \| Neoplasm solid	18 Sultain, 2019	Ìre 2
NCT04142437	Bayer	Tumor soladach adhartach no meatastatach gu h-ionadail a ’caladh NTRK Gene Fusion	3 Giblean, 2020
NCT03155620	Institiud Nàiseanta Ailse (NCI)	Neoplasm Solid Malignant adhartach \| Ann Arbor Ìre III Lymphoma neo-Hodgkin \| Ann Arbor Ìre IV Lymphoma neo-Hodgkin \| Sarcoma histiocytic \| Xanthogranuloma òg \| Langerhans Cell Histiocytosis \| Malignant Glioma \| Ath-chuairteachadh Ath-bheòthachaidh \| Ath-chuairteachadh Ath-chuairteachadh \| Hepatoblastoma cunbhalach \| Sarcoma fìne bog bog ath-chuairteach \| Sarcoma teasairginn teasairginn \| Glioma teasfhulangach \| Hepatoblastoma teasfhulangach \| histiocytosis cealla teasfhulangach \| Tumor cealla germ malignant teasfhulangach \| Neoplasm soladach teas-meadhain teasfhulangach \| Medulloblastoma teasairginn \| Refractory Refractory \| ctory Tumor Neuroectodermal Primitive Primitive \| Refractory Primary Central Nervous System Neoplasm \| Tumor Rhabdoid teasfhulangach \| Ìre IVA Osteosarcoma AJCC v7 \| Ìre IVB Osteosarcoma AJCC v7 \| Wilms Tumor	24 Iuchar 2017	Ìre 2