ATC Group: L01E Protein kinase inhibitors

Abemaciclib is a potent and selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), and most active against Cyclin D1/CDK4 in enzymatic assays. Abemaciclib prevents retinoblastoma protein (Rb) phosphorylation, blocking cell cycle progression from the G1 to the S-phase of cell division, leading to suppression of tumour growth.

Acalabrutinib is a small-molecule inhibitor of BTK (Bruton’s tyrosine kinase). Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. In nonclinical studies, acalabrutinib inhibited BTK-mediated activation of downstream signaling proteins CD86 and CD69 and inhibited malignant B-cell proliferation and tumor growth in mouse xenograft models.

Afatinib is a potent and selective, irreversible ErbB Family Blocker. Afatinib covalently binds to and irreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4.

Alectinib is a highly selective and potent ALK and rearranged during transfection (RET) tyrosine kinase inhibitor. In pre-clinical studies, inhibition of ALK tyrosine kinase activity led to blockage of downstream signalling pathways including signal transducer and activator of transcription 3 (STAT 3) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and induction of tumour cell death (apoptosis).

Alpelisib is an α-specific class I phosphatidylinositol3kinase (PI3Kα) inhibitor. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα and AKT-signalling, cellular transformation and the generation of tumours in in vitro and in vivo models.

Asciminib is a potent inhibitor of ABL/BCR::ABL1 tyrosine kinase. Asciminib inhibits the ABL1 kinase activity of the BCR::ABL1 fusion protein by specifically targeting the ABL myristoyl pocket.

Axitinib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2 and VEGFR-3. These receptors are implicated in pathologic angiogenesis, tumour growth, and metastatic progression of cancer. Axitinib has been shown to potently inhibit VEGF-mediated endothelial cell proliferation and survival.

Binimetinib is an ATP-uncompetitive, reversible inhibitor of the kinase activity of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. Binimetinib inhibits activation of MEK by BRAF and inhibits MEK kinase activity.

Bosutinib belongs to a pharmacological class of medicinal products known as kinase inhibitors. Bosutinib inhibits the abnormal BCR-ABL kinase that promotes CML. Modeling studies indicate that bosutinib binds the kinase domain of BCR-ABL. Bosutinib is also an inhibitor of Src family kinases including Src, Lyn and Hck. Bosutinib minimally inhibits platelet-derived growth factor (PDGF) receptor and c-Kit. In in vitro studies, bosutinib inhibits proliferation and survival of established CML cell lines, Ph+ ALL cell lines, and patient-derived primary primitive CML cells.

Brigatinib is a tyrosine kinase inhibitor that targets ALK, c-ros oncogene 1 (ROS1), and insulin-like growth factor 1 receptor (IGF-1R). It is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).

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.

Ceritinib is an orally highly selective and potent ALK inhibitor. Ceritinib inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of downstream signalling proteins and proliferation of ALK-dependent cancer cells both in vitro and in vivo.

Cobimetinib is a reversible, selective, allosteric, oral inhibitor that blocks the mitogen-activated protein kinase (MAPK) pathway by targeting the mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK 2 which results in inhibition of phosphorylation of the extracellular signal-regulated kinase (ERK) 1 and ERK 2. Therefore, cobimetinib blocks the cell proliferation induced by the MAPK pathway through inhibition of the MEK1/2 signalling node.

Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Copanlisib has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines.

Crizotinib is a selective small-molecule inhibitor of the ALK receptor tyrosine kinase (RTK) and its oncogenic variants (i.e. ALK fusion events and selected ALK mutations). Crizotinib is also an inhibitor of the Hepatocyte Growth Factor Receptor (HGFR, c-Met) RTK, ROS1 (c-ros) and Recepteur d’Origine Nantais (RON) RTK.

Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway. BRAF mutations have been identified at a high frequency in specific cancers, including approximately 50% of melanoma. Dabrafenib demonstrated suppression of a downstream pharmacodynamic biomarker (phosphorylated ERK) and inhibited cell growth of BRAF V600 mutant melanoma cell lines, in vitro and in animal models.

Dacomitinib is a pan-human epidermal growth factor receptor (HER) (EGFR/HER1, HER2, and HER4) inhibitor, with activity against mutated EGFR with deletions in exon 19 or the L858R substitution in exon 21. Dacomitinib binds selectively and irreversibly to its HER family targets thereby providing prolonged inhibition.

Dasatinib inhibits the activity of the BCR-ABL kinase and SRC family kinases along with a number of other selected oncogenic kinases including c-KIT, ephrin (EPH) receptor kinases, and PDGFβ receptor. Dasatinib is a potent, subnanomolar inhibitor of the BCR-ABL kinase with potency at concentration of 0.6-0.8 nM. It binds to both the inactive and active conformations of the BCR-ABL enzyme.

Duvelisib is a dual inhibitor of phosphatidylinositol 3-kinase p110δ (PI3K-δ) and PI3K-γ. PI3K-δ inhibition directly reduces proliferation and survival of malignant B-cell lines and primary CLL tumour cells, while PI3K-γ inhibition reduces the activity of CD4+ T cells and macrophages in the tumor microenvironment to support the malignant B cells.

Encorafenib is a potent and highly selective ATP-competitive small molecule RAF kinase inhibitor. Encorafenib suppresses the RAF/MEK/ERK pathway in tumour cells expressing several mutated forms of BRAF kinase (V600E, D and K). Specifically, encorafenib inhibits in vitro and in vivo BRAF^V600E,DandK mutant melanoma cell growth.

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.

Erdafitinib is a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. Erdafitinib increases serum phosphate concentration, a secondary effect of FGFR inhibition.

Erlotinib is an epidermal growth factor receptor/human epidermal growth factor receptor type 1 (EGFR also known as HER1) tyrosine kinase inhibitor. Erlotinib potently inhibits the intracellular phosphorylation of EGFR. EGFR is expressed on the cell surface of normal cells and cancer cells. Due to the blocking of downstream-signaling, the proliferation of cells is stopped, and cell death is induced through the intrinsic apoptotic pathway.

Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-threonine kinase, the activity of which is known to be upregulated in a number of human cancers.

Fedratinib is a kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib reduced JAK2-mediated phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited malignant cell proliferation in vitro and in vivo.

Fruquintinib is a selective tyrosine kinase inhibitor of VEGFR-1, -2, and -3 with antitumor effects resulting from suppression of tumour angiogenesis.

Constitutive fibroblast growth factor receptor (FGFR) signalling can support the proliferation and survival of malignant cells. Futibatinib is a tyrosine kinase inhibitor that irreversibly inhibits FGFR 1, 2, 3, and 4 by covalent binding.

Gefitinib is a selective small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase and is an effective treatment for patients with tumours with activating mutations of the EGFR tyrosine kinase domain regardless of line of therapy. No clinically relevant activity has been shown in patients with known EGFR mutation-negative tumours.

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.

Ibrutinib is a potent, small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). BTK, a member of the Tec kinase family, is an important signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. Preclinical studies have shown that ibrutinib effectively inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.

Idelalisib inhibits phosphatidylinositol 3-kinase p110δ (PI3Kδ), which is hyperactive in B-cell malignancies and is central to multiple signalling pathways that drive proliferation, survival, homing, and retention of malignant cells in lymphoid tissues and bone marrow. Idelalisib induces apoptosis and inhibits proliferation in cell lines derived from malignant B-cells and in primary tumour cells.

Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at the in vitro, cellular and in vivo levels.

Lapatinib, a 4-anilinoquinazoline, is an inhibitor of the intracellular tyrosine kinase domains of both EGFR (ErbB1) and of HER2 (ErbB2) receptors (estimated Ki^app values of 3nM and 13nM, respectively) with a slow off-rate from these receptors (half-life greater than or equal to 300 minutes). Lapatinib inhibits ErbB-driven tumour cell growth in vitro and in various animal models.

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.

Lorlatinib is a selective, adenosine triphosphate (ATP)-competitive inhibitor of ALK and c-ros oncogene 1 (ROS1) tyrosine kinases.

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.

Momelotinib and its major human circulating metabolite (M21), are inhibitors of wild type Janus Kinase 1 and 2 (JAK1/JAK2) and mutant JAK2^V617F, which contribute to signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function. Momelotinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from patients with myelofibrosis and inhibits hepcidin. Additionally, momelotinib and M21 are direct inhibitors of ACVR1, which further down regulates liver hepcidin expression resulting in increased iron availability and red blood cell production.

Neratinib is an irreversible pan–erythroblastic leukaemia viral oncogene homolog (ERBB) tyrosine kinase inhibitor (TKI) that blocks mitogenic growth factor signal transduction through covalent, high affinity binding to the ATP binding site of 3 epidermal growth factor receptors (EGFRs): EGFR (encoded by ERBB1), HER2 (encoded by ERBB2), and HER4 (encoded by ERBB4) or their active heterodimers with HER3 (encoded by ERBB3). This results in sustained inhibition of these growth promoting pathways with HER2-amplified or over-expressed, or HER2-mutant breast cancers.

Nilotinib is a potent inhibitor of the ABL tyrosine kinase activity of the BCR-ABL oncoprotein. Nilotinib selectively inhibits the proliferation and induces apoptosis in cell lines and in primary Philadelphia-chromosome positive leukaemia cells from CML patients. In murine models of CML, as a single agent nilotinib reduces tumour burden and prolongs survival following oral administration.

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).

Osimertinib is a Tyrosine Kinase Inhibitor (TKI). It is an irreversible inhibitor of EGFRs harboring sensitising-mutations (EGFRm) and TKI-resistance mutation T790M. In vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against EGFR across a range of all clinically relevant EGFR sensitising-mutant and T790M mutant NSCLC cell lines.

Palbociclib is a highly selective, reversible inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Through inhibition of CDK4/6, palbociclib reduced cellular proliferation by blocking progression of the cell from G1 into S phase of the cell cycle. Testing of palbociclib in a panel of molecularly profiled breast cancer cell lines revealed high activity against luminal breast cancers, particularly ER-positive breast cancers.

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.

Pemigatinib is a kinase inhibitor of FGFR1, 2 and 3 which inhibits FGFR phosphorylation and signalling and decreases cell viability in cells expressing FGFR genetic alterations, including point mutations, amplifications, and fusions or rearrangements. FGFR2 fusions/rearrangements are strong oncogenic drivers and are the most common FGFR alteration occurring, almost exclusively, in 10-16% of intrahepatic cholangiocarcinoma (CCA).

Pirtobrutinib is a reversible, noncovalent inhibitor of BTK. BTK is a signalling protein of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Pirtobrutinib binds to wild type BTK as well as BTK harboring C481 mutations leading to inhibition of BTK kinase activity.

Ponatinib is a potent pan BCR-ABL inhibitor with structural elements, including a carbon-carbon triple-bond, that enable high affinity binding to native BCR-ABL and mutant forms of the ABL kinase. Ponatinib inhibits the tyrosine kinase activity of ABL and T315I mutant ABL with IC₅₀ values of 0.4 and 2.0 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.

Ribociclib is a selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, resulting in 50% inhibition (IC₅₀) values of 0.01 (4.3 ng/ml) and 0.039 μM (16.9 ng/ml) in biochemical assays, respectively. These kinases are activated upon binding to D-cyclins and play a crucial role in signalling pathways which lead to cell cycle progression and cellular proliferation.

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.

Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 (IC₅₀ values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively). These mediate the signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function. Ruxolitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from healthy subjects, MF patients and PV patients.

Selumetinib is a selective inhibitor of mitogen activated protein kinase kinases 1 and 2 (MEK ½). Selumetinib blocks MEK activity and the RAF-MEK-ERK pathway. Therefore, MEK inhibition can block the proliferation and survival of tumour cells in which the RAF-MEK-ERK pathway is activated.

Sirolimus inhibits T-cell activation induced by most stimuli, by blocking calcium-dependent and calcium-independent intracellular signal transduction. Studies demonstrated that its effects are mediated by a mechanism that is different from that of ciclosporin, tacrolimus, and other immunosuppressive agents.

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.

Temsirolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein/temsirolimus complex binds and inhibits the activity of mTOR that controls cell division. In vitro, at high concentrations (10-20 M), temsirolimus can bind and inhibit mTOR in the absence of FKBP-12. When mTOR activity is inhibited, its ability to phosphorylate, and thereby control the activity of protein translation factors (4E-BP1 and S6K, both downstream of mTOR in the P13 kinase/AKT pathway) that control cell division, is blocked.

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.

Tivozanib potently and selectively blocks all 3 Vascular Endothelial Growth Factor receptors (VEGFR) and has been shown to block various VEGF-induced biochemical and biologic responses in vitro. By blocking VEGF-induced VEGFR activation, tivozanib inhibits angiogenesis and vascular permeability in tumour tissues, leading to inhibition of tumour growth in vivo.

Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. In melanoma and other cancers, this pathway is often activated by mutated forms of BRAF which activates MEK. Trametinib inhibits activation of MEK by BRAF and inhibits MEK kinase activity.

Tucatinib is a tyrosine kinase inhibitor of HER2. It is used in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer.

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.

Vemurafenib is an inhibitor of BRAF serine-threonine kinase. Mutations in the BRAF gene result in constitutive activation of BRAF proteins, which can cause cell proliferation without associated growth factors. Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test.

Zanubrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). Zanubrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is a signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.