ATC Group: L01EX Other protein kinase inhibitors

Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumour growth and angiogenesis, pathologic bone remodeling, drug resistance, and metastatic progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine kinases including the GAS6 receptor (AXL), RET, ROS1, TYRO3, MER, the stem cell factor receptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3), and TIE-2.

Capivasertib is a potent, selective inhibitor of the kinase activity of all 3 isoforms of serine/threonine kinase AKT (AKT1, AKT2 and AKT3). AKT activation in tumours is a result of upstream activation from other signalling pathways, mutations of AKT1, loss of Phosphatase and Tensin Homolog (PTEN) function and mutations in the catalytic subunit of PI3K (PIK3CA). Capivasertib reduces growth of cell lines derived from solid tumours and haematological disease, including breast cancer cell lines with and without PIK3CA or AKT1 mutations, or PTEN alterations.

Capmatinib is an inhibitor of the MET receptor tyrosine kinase. Capmatinib inhibits MET phosphorylation (both autophosphorylation and phosphorylation triggered by the ligand hepatocyte growth factor [HGF]), MET-mediated phosphorylation of downstream signalling proteins, as well as proliferation and survival of MET-dependent cancer cells.

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases TRKA, TRKB and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2 and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS (ROS1), and anaplastic lymphoma kinase (ALK). Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumour types, including subcutaneous and intracranial tumours, harbouring NTRK, ROS1, and ALK fusion genes.

Gilteritinib fumarate is a FLT3 and AXL inhibitor. Gilteritinib inhibits FLT3 receptor signalling and proliferation in cells exogenously expressing FLT3 including FLT3-ITD, FLT3-D835Y, and FLT3-ITD-D835Y, and it induces apoptosis in leukemic cells expressing FLT3-ITD.

Larotrectinib is an adenosine triphosphate (ATP)-competitive and selective tropomyosin receptor kinase (TRK) inhibitor. The TRK family of proteins, TRKA, TRKB, and TRKC, is encoded by NTRK1, NTRK2 and NTRK3 genes. Larotrectinib was rationally designed to avoid activity with off-target kinases. It is indicated for the treatment of adult and paediatric patients with solid tumours that display a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion.

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor (PDGF) receptor PDGFRα, KIT, and RET.

Midostaurin inhibits multiple receptor tyrosine kinases, including FLT3 and KIT kinase. Midostaurin inhibits FLT3 receptor signalling and induces cell cycle arrest and apoptosis in leukaemic cells expressing FLT3 ITD or TKD mutant receptors or over-expressing FLT3 wild type receptors.

Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and β) and fibroblast growth factor receptors (FGFR 1-3) kinase activity. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signalling which is crucial for the proliferation and survival of endothelial as well as perivascular cells (pericytes and vascular smooth muscle cells).

Pazopanib is an orally administered, potent multi-target tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, platelet-derived growth factor (PDGFR) -α and -β, and stem cell factor receptor (c-KIT), with IC₅₀ values of 10, 30, 47, 71, 84 and 74 nM, respectively.

Quizartinib is an inhibitor of the receptor tyrosine kinase FLT3. Quizartinib and its major metabolite AC886 competitively bind to the adenosine triphosphate (ATP) binding pocket of FLT3 with high affinity. Quizartinib and AC886 inhibit FLT3 kinase activity, preventing autophosphorylation of the receptor, thereby inhibiting further downstream FLT3 receptor signalling and blocking FLT3-ITDdependent cell proliferation.

Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAF^V600E), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R). Regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumours, and thereby blocks tumour cell proliferation.

Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and of the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. Fusion proteins that include ROS1 domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Repotrectinib exhibited anti-tumor activity in cultured cells expressing ROS1 fusions and mutations including SDC4-ROS1, SDC4-ROS1^G2032R, CD74-ROS1, CD74-ROS1^G2032R, CD74-ROS1^D2033N, and CD74-ROS1^L2026M.

Ripretinib is a novel tyrosine kinase inhibitor that inhibits KIT proto-oncogene receptor tyrosine kinase and PDGFRA kinase, including wild type, primary, and secondary mutations. Ripretinib also inhibits other kinases in vitro, such as PDGFRB, TIE2, VEGFR2, and BRAF.

Sorafenib is a multikinase inhibitor which has demonstrated both anti-proliferative and anti-angiogenic properties in vitro and in vivo. Sorafenib inhibits the activity of targets present in the tumour cell (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-β).

Sunitinib inhibits multiple RTKs that are implicated in tumour growth, neoangiogenesis, and metastatic progression of cancer.

Tepotinib is a reversible Type I adenosine triphosphate (ATP)-competitive small molecule inhibitor of MET. Tepotinib blocked MET phosphorylation and MET-dependent downstream signalling in a dose-dependent manner. Tepotinib demonstrated pronounced anti-tumour activity in tumours with oncogenic activation of MET, such as METex14 skipping alterations.

Vandetanib is a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2 also known as kinase insert domain containing receptor [KDR]), epidermal growth factor receptor (EGFR) and RET tyrosine kinases. Vandetanib is also a sub-micromolar inhibitor of vascular endothelial receptor-3 tyrosine kinase.