China LOXO-101 1223403-58-4 bahlahisi le ba fanang ka thepa

LOXO-101 1223403-58-4

Tlhaloso e Khutšoanyane:

Lebitso la API	Sesupo	Moqapi	Letsatsi la ho Fela ka Patent (The US)
LOXO-101 1223403-58-4	Lithethefatsi tsa oncology	Loxo Oncology	Mphalane 21,2029

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IC50: mofuta o tlase oa nanomolar bakeng sa thibelo ea litho tsohle tsa lelapa la TRK

LOXO-101 ke inhibitor ea tropomyosin receptor kinases (TRK).

Lelapa la TRK la li-receptor tsa neurotrophin le li-neurotrophin ligands li laola kholo ea methapo, phapang le pholoho.

In vitro: Thutong e fetileng, LOXO-101 e ile ea hlahlojoa bakeng sa tšebetso ea enzyme ea off-target kinase khahlano le karolo ea li-kinase tse seng tsa TRK nakong ea likhahla tsa 1,000 nM le ATP ho potoloha Km. Liphetho li bonts'itse hore LOXO-101 e na le thibelo e kholo ho feta 50% bakeng sa e le 'ngoe feela e seng TRK kinase, eo e neng e le TNK2 le IC50 ea 576 nM. Ho feta moo, ho ne ho se na thibelo e nepahetseng ea hERG kapa tlhahlobo e telele ea QT [1].

In vivo: Phuputso ea liphoofolo e fumane hore LOXO-101 e khona ho thibela kholo ea hlahala ea vivo. Litoeba tse hlobotseng tsa Athymic tse entsoeng ka lisele tsa KM12 li ne li phekoloa ka molomo ka LOXO-101 letsatsi le letsatsi bakeng sa libeke tse 2, mme ho ile ha bonoa thibelo ea ts'oaetso e itšetlehileng ka tekanyetso, e bonts'a bokhoni ba LOXO-101 ho thibela kholo ea in-vivo hlahala [1].

Teko ea bongaka: Thupelo ea keketseho ea tekanyetso ea litekanyetso ho bakuli ba nang le lihlahala tse tiileng tse tsoetseng pele (ClinicalTrials.gov no. NCT02122913) e entsoe ka 2014 ho lekola polokeho le PK ea LOXO-101. Bakuli ba tšeloa hanngoe kapa habeli ka letsatsi bakeng sa matsatsi a 28 a li-dosing tse tsoelang pele lihlopheng tse ntseng li eketseha. Lintlha tsa pele tsa PK le polokeho li bonts'a hore litekanyetso tsa mahala tsa plasma tsa LOXO-101 li maemong a amanang le bioloji ho thibela li-oncogenes tsa TRK. Phuputsong ena, mokuli oa pele ebile e le eena feela o bontšitse fusion ea TRK le khatello e potlakileng ea hlahala ea kliniki e bonoeng ka kalafo ea LOXO-101 [1].

Tšupiso:
[1] Doebele RC et al. Fusion ea Oncogenic NTRK ho Mokuli ea nang le Soft-Tissue Sarcoma e nang le Karabelo ho Tropomyosin-Related Kinase Inhibitor LOXO-101. Kankere Discov. 2015 Oct; 5 (10): 1049-57.

Tlhaloso

Larotrectinib (LOXO-101) ke tlholisano ea molomo ea ATP, inhibitor e khethang ea li-receptor tsa malapa tse amanang le tropomyosin (TRK), e nang le li-nanomolar tse tlase tsa 50% tse thibelang li-isoforms tse tharo (TRKA, B, le C).

Teko ea Bongaka

Nomoro ea NCT	Mofani	Boemo	Letsatsi la qalo	Phase
NCT03025360	Monghali Bayer	Lihlahala tse bolokang NTRK Fusion
NCT02637687	Monghali Bayer	Matšoafo a Tiileng a Bolokang NTRK Fusion	La 16 Tšitoe 2015	Phase 1 \| Phase 2
NCT02122913	Monghali Bayer	Matšoafo a Tiileng a Bolokang NTRK Fusion	La 4 Mots'eanong, 2014	Karolo ea 1
NCT03213704	Setsi sa Naha ea Kankere (NCI)	Advanced Malignant Solid Neoplasm \| Ependymoma e iphetang \| Ewing Sarcoma + Peripheral Primitive Neuroectodermal Tumor \| Glioma e iphetang \| Hepatoblastoma e iphetang \| Langerhans Cell Histiocytosis \| Kankere ea Likokoana-hloko ea Likokoana-hloko ea Malapa a Kopaneng \| Non-Hodgkin Lymphoma \| Osteosarcoma e iphetang \| Rhabdoid Tumor e iphetang Malignant Glioma \| Refractory Malignant Solid Neoplasm \| Refractory Neuroblastoma \| Refractory Non-Hodgkin Lymphoma \| Refractory Osteosarcoma \| Refractory Primary Central Nervous System Neoplasm \| Refractory Rhabdoid Tumor \| Refractory Rhabdomyosarcoma \| Wilms Tumor	La 24 Phupu, 2017	Karolo ea 2
NCT02465060	Setsi sa Naha ea Kankere (NCI)	Sefuba se tsoetseng pele sa malignant Solid \| Malignant Uterine Neoplasm \| Melanoma \| Ovarian Carcinoma \| Pancreatic Carcinoma \| Plasma Cell Myeloma \| Prostate Carcinoma \| Rectal Carcinoma \| Recurrent Bladder Carcinoma \| Recrerent Breast Carcinoma \| Kankere ea Kankere ea Kankere \| Recurrent Colon Carcinoma \| Recurrent Carcinoma Carcinoma \| Glioma e iphetang Letlalo la Carcinoma le Khutlelang \| Gland Gland e iphetang Carcinoma \| Kankere ea Uterine Corpus e Phelang \| Refractory Lymphoma \| Refractory Malignant Solid Neoplasm \| Refractory Plasma Cell Myeloma \| Skin Carcinoma \| Thyroid Gland Carcinoma \| Uterine Corpus Cancer	La 12 Phato, 2015	Karolo ea 2
NCT03834961	Sehlopha sa Bana sa Oncology \| Setsi sa Naha ea Kankere (NCI)	Neoplasm ea Sisteme ea Bohareng \| Infantile Fibrosarcoma \| Leukemia e Phelang Haholo \| Leukemia e Ikemetseng e Hlahang \| Neoplasm e Tiileng	Loetse 18, 2019	Karolo ea 2
NCT04142437	Monghali Bayer	Hlahala ea Haufi kapa Metastatic Solid Tumor e bolokang NTRK Gene Fusion	La 3 Mmesa, 2020
NCT03155620	Setsi sa Naha ea Kankere (NCI)	Sefuba se tsoetseng pele sa malignant Solid Hepatoblastoma e iphetang \| Langerhans Cell Histiocytosis e iphetang \| Tissue Sarcoma e Khubelu ea Khale ctory Peripheral Primitive Neuroectodermal Tumor \| Refractory Primary Central Nervous System Neoplasm \| Refractory Rhabdoid Tumor \| Refractory Rhabdomyosarcoma \| Rhabdoid Tumor \| Stage III Osteosarcoma AJCC v7 \| Stage III Bonolo ba Lisele tsa Sarcoma AJCC v7 \| Mothati oa IV OA Oste \| Mothati oa IVA Osteosarcoma AJCC v7 \| Mothati oa IVB Osteosarcoma AJCC v7 \| Wilms Tumor	La 24 Phupu, 2017	Karolo ea 2