Angiopoietin receptors are receptors that bind angiopoietin, they are receptor tyrosine kinases (RTKs). TIE-1 and TIE-2 (TEK kinase) comprise the cell-surface receptors that bind and are activated by the angiopoietins, (Ang1, Ang2, Ang3, Ang4). The angiopoietins are protein growth factors that regulate angiogenesis, the formation of blood vessels.
The angiopoietin/tunica interna endothelial cell kinase (TIE) signaling axis have become additional targets for therapeutic intervention for angiogenic pathways in cancer cells. BAY-826 inhibits TIE-2 phosphorylation in vitro and in vivo as demonstrated by suppression of Angiopoietin-1- or Na3 VO4 -induced TIE-2 phosphorylation in glioma cells or extracts of lungs from BAY-826-treated mice. Pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, inhibited the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells.
Selective small molecule inhibitors of Tie-2 kinase are important tools for the validation of Tie-2 signaling in pathological angiogenesis.
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BAY-826 (BAY826) is a novel selective, highly potent, orally available TIE-2 inhibitor (dissociation constant=1.6 nM); binds with similar high affinity to only 4 of 456 kinases, namely, TIE-1,DDR1, DDR2, and LOK (dissociation constant=0.9, 0.4, 1.3, and 5.9 nM), BAY-826 is highly selective against other angiogenic kinases, such as VEGFR, FGFR, or PDGFR, and affects VEGF-stimulated proliferation of HUVEC only at lM concentrations; inhibits TIE-2 phosphorylation in vitro and in vivo as demonstrated by suppression of Angiopoietin-1- or Na3 VO4 -induced TIE-2 phosphorylation in glioma cells or extracts of lungs from BAY-826-treated mice; improves tumor control in syngeneic mouse glioma models.
CE-245677 is a potent, selective, orally active, dual Tie2/Trk kinase inhibitor with IC50 of 4.7 nM, 1 nM for Tie2 and TrkA/B, respectively; displays >100-fold selectivity against a panel of angiogenic receptor tyrosine kinases (e.g. KDR, PDGFR, FGFR).
Pexmetinib (ARRY-614) is a potent, orally active, dual Tie-2/p38 MAPK inhibitor with IC50 of 1, 26 and 35 nM for Tie-2, p38α and p38β, respectively; demonstrates in vitro mechanistic models (Angpt-1 or anisomycin-stimulated HUVEC) as well as functional readouts (LPS-induced TNF-alpha release from human PBMCs) with IC50 of 2282 nM and 172 nM for Tie2 and p38, respectively; abrogates cytokine mediated myelosuppresive effects in hematopoietic cells; inhibits leukemic cell proliferation and stimulates hematopoietic activity in MDS; inhibits LPS-induced TNF-alpha release) murine models .
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