||UNC2541 is a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket. UNC2541 showed IC50 MerTH=4.4 nM; IC50 AXL = 120 nM; IC50 TYRO3 = 220 nM; IC50 FLT3 = 320 nM.
||RU-302 is a novel pan-tam inhibitor, blocking the interface between tam ig1 ectodomain and gas6 lg domain, potently inhibiting axl reporter cell lines and native tam receptors cancer cell lines
||CT-053, also known as DE-120, is a VEGF and PDGF inhibitor potentially for the treatment of wet age-related macular degeneration.
||SGI-7079 is a potent and selective Axl inhibitor with potential anticancer activity. SGI-7079 effectively inhibited Axl activation in the presence of exogenous Gas6 ligand. SGI-7079 inhibited tumor growth in a dose dependent manner. Axl is a potential therapeutic target for overcoming EGFR inhibitor resistance.
||2-D08 is a synthetic flavone that inhibits sumoylation. 2-D08 showed anti-aggregatory and neuroprotective effect
||Dubermatinib, also known as TP-0903, is a potent and selective AXL inhibitor. TP-0903 induces massive apoptosis in CLL B cells with LD50 values of nanomolar ranges. Combination of TP-0903 with BTK inhibitors augments CLL B-cell apoptosis AXL overexpression is a reoccurring theme observed in multiple tumor types that have acquired resistance to various agents. Treatment of cancer cells with TP-0903 reverses the mesenchymal phenotype in multiple models and sensitizes cancer cells to treatment with other targeted agents. Administration of TP-0903 either as a single agent or in combination with BTK inhibitors may be effective in treating patients with CLL.
||NPS-1034 is a novel MET inhibitor, which inhibits the activated MET receptor and its constitutively active mutants. NPS-1034, inhibits various constitutively active mutant forms of MET as well as HGF-activated wild-type MET. NPS-1034 inhibited the proliferation of cells expressing activated MET and promoted the regression of tumors formed from such cells in a mouse xenograft model through anti-angiogenic and pro-apoptotic actions. NPS-1034 also inhibited HGF-stimulated activation of MET signaling in the presence or absence of serum. Notably, NPS-1034 inhibited three MET variants that are resistant to the MET inhibitors SU11274, NVP-BVU972, and PHA665752.
||Glesatinib, also known as MGCD-265, is an orally bioavailable, small-molecule, multitargeted tyrosine kinase inhibitor with potential antineoplastic activity. MGCD265 binds to and inhibits the phosphorylation of several receptor tyrosine kinases (RTKs), including the c-Met receptor (hepatocyte growth factor receptor); the Tek/Tie-2 receptor; vascular endothelial growth factor receptor (VEGFR) types 1, 2, and 3; and the macrophage-stimulating 1 receptor (MST1R or RON).
|| CEP-40783, also known as RXDX-106, is a potent, selective and orally available inhibitor of AXL and c-Met with IC50 values of 7 nM and 12 nM, respectively for use in breast, non-small cell lung (NSCLC), and pancreatic cancers.
||BGB-324, also known as R428 or Bemcentinib, is a selective small molecule inhibitor of Axl kinase, which showed activity to blocks tumor spread and prolongs survival in models of metastatic breast cancer. The receptor tyrosine kinase Axl may play an important role in cancer progression, invasion, metastasis, drug resistance, and patient mortality. R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production.
||Gilteritinib, also known as ASP2215, is a potent FLT3/AXL inhibitor, which showed potent antileukemic activity against AML with either or both FLT3-ITD and FLT3-D835 mutations. In invitro, among the 78 tyrosine kinases tested, ASP2215 inhibited FLT3, LTK, ALK, and AXL kinases by over 50% at 1 nM with an IC50 value of 0.29 nM for FLT3, approximately 800-fold more potent than for c-KIT, the inhibition of which is linked to a potential risk of myelosuppression. ASP2215 inhibited the growth of MV4-11 cells, which harbor FLT3-ITD, with an IC50 value of 0.92 nM, accompanied with inhibition of pFLT3, pAKT, pSTAT5, pERK, and pS6. ASP2215 decreased tumor burden in bone marrow and prolonged the survival of mice intravenously transplanted with MV4-11 cells. ASP2215 may have potential use in treating AML.
||UNC2881 is a potent Mer kinase inhibitor. UNC2281 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with UNC2281 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, UNC2881 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.
||UNC2250 is a potent and selective Mer Kinase inhibitor. When applied to live cells, UNC2250 inhibited steady-state phosphorylation of endogenous Mer with an IC50 of 9.8 nM and blocked ligand-stimulated activation of a chimeric EGFR-Mer protein. Treatment with UNC2250 also resulted in decreased colony-forming potential in rhabdoid and NSCLC tumor cells, thereby demonstrating functional antitumor activity. The results provide a rationale for further investigation of UNC2250 for therapeutic application in patients with cancer.
||LDC1267 is a potent and selective TAM kinase inhibitor. LDC1267 displays lower activity against Met, Aurora B, Lck, Src, and CDK8. LDC1267 markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo.
||BMS-777607, also known as BMS-817378 and ASLAN-002, a Met tyrosine kinase inhibitor, is an inhibitor of MET tyrosine kinase with potential antineoplastic activity. MET tyrosine kinase inhibitor BMS-777607 binds to c-Met protein, or hepatocyte growth factor receptor (HGFR), preventing binding of hepatocyte growth factor (HGF) and disrupting the MET signaling pathway; this agent may induce cell death in tumor cells expressing c-Met. c-Met, a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays an important role in tumor cell proliferation, survival, invasion, and metastasis, and in tumor angiogenesis.
||Cabozantinib, also known as XL-184 or BMS-907351, is an orally bioavailable, small molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Cabozantinib strongly binds to and inhibits several tyrosine receptor kinases. Specifically, cabozantinib appears to have a strong affinity for the hepatocyte growth factor receptor (Met) and vascular endothelial growth factor receptor 2 (VEGFR2), which may result in inhibition of tumor growth and angiogenesis, and tumor regression. Cabozantinib was approved by the U.S. FDA in November 2012 for the treatment of medullary thyroid cancer.
||BGB-324; Bemcentinib; R428
||BGB-324, also known as R428 or Bemcentinib, is a selective small molecule inhibitor of Axl kinase, which showed activity to blocks tumor spread and prolongs survival in models of metastatic breast cancer.