TGX-221

TGX-221 is a potent inhibitor of (phosphatidylinositol 3-kinases) PI3K which specifically inhibits PI3K -p110β isoform with IC50 value of 8.5 nM [1].

In J774.2 macrophage cells, TGX-221 has been demonstrated to reduce insulin-induced phosphorylation of Ser473?of protein kinase B (PKB). While in in CHO-IR and 3T3-L1 cells, TGX-221 has no effect on PKB phosphprylation [1].

In vivo, TGX-221 significantly improved blood flow in FeCl3-induced arterial thrombosis as well as?increased tail and renal bleeding times in mice. In addition, TGX-221 has revealed to disrupt CFRs in a Folts model of arterial thrombosis in male Sprague-Dawley rats [2].?

References:
[1] Chaussade C1,?Rewcastle GW,?Kendall JD,?Denny WA,?Cho K,?Gr?nning LM,?Chong ML,?Anagnostou SH,Jackson SP,?Daniele N,?Shepherd PR.

Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling. Biochem J.?2007 Jun 15;404(3):449-58.

[2] Bird JE1,?Smith PL,?Bostwick JS,?Shipkova P,?Schumacher WA.

Bleeding response induced by anti-thrombotic doses of a phosphoinositide 3-kinase (PI3K)-β inhibitor in mice. Thromb Res.?2011 Jun;127(6):560-4.

Activation of phosphatidylinositol 3-kinase beta by the platelet collagen receptors integrin alpha2beta1 and GPVI: The role of Pyk2 and c-Cbl.[Pubmed:25960397]

Biochim Biophys Acta. 2015 Aug;1853(8):1879-88.

Phosphatidylinositol 3-kinasebeta (PI3Kbeta) plays a predominant role in integrin outside-in signaling and in platelet activation by GPVI engagement. We have shown that the tyrosine kinase Pyk2 mediates PI3Kbeta activation downstream of integrin alphaIIbbeta3, and promotes the phosphorylation of the PI3K-associated adaptor protein c-Cbl. In this study, we compared the functional correlation between Pyk2 and PI3Kbeta upon recruitment of the two main platelet collagen receptors, integrin alpha2beta1 and GPVI. PI3Kbeta-mediated phosphorylation of Akt was inhibited in Pyk2-deficient platelets adherent to monomeric collagen through integrin alpha2beta1, but occurred normally upon GPVI ligation. Integrin alpha2beta1 engagement led to Pyk2-independent association of c-Cbl with PI3K. However, c-Cbl was not phosphorylated in adherent platelets, and phosphorylation of Akt occurred normally in c-Cbl-deficient platelets, indicating that the c-Cbl is dispensable for Pyk2-mediated PI3Kbeta activation. Stimulation of platelets with CRP, a selective GPVI ligand, induced c-Cbl phosphorylation in the absence of Pyk2, but failed to promote its association with PI3K. Pyk2 activation was completely abrogated in PI3KbetaKD, but not in PI3KgammaKD platelets, and was strongly inhibited by Src kinases and phospholipase C inhibitors, and by BAPTA-AM. The absence of PI3Kbeta activity also hampered GPVI-induced tyrosine-phosphorylation and activation of PLCgamma2, preventing intracellular Ca2+ increase and phosphorylation of pleckstrin. Moreover, GPVI-induced intracellular Ca2+ increase and pleckstrin phosphorylation were also strongly inhibited in human platelets treated with the PI3Kbeta inhibitor TGX-221. These results outline important differences in the regulation of PI3Kbeta by GPVI and integrin alpha2beta1 and suggest that inhibition of Pyk2 may target PI3Kbeta activation in a selective context of platelet stimulation.

Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils.[Pubmed:15878979]

Blood. 2005 Aug 15;106(4):1432-40.

It is well established that preexposure of human neutrophils to proinflammatory cytokines markedly augments the production of reactive oxygen species (ROS) to subsequent stimuli. This priming event is thought to be critical for localizing ROS to the vicinity of the inflammation, maximizing their role in the resolution of the inflammation, and minimizing the damage to surrounding tissue. We have used a new generation of isoform-selective phosphoinositide 3-kinase (PI3K) inhibitors to show that ROS production under these circumstances is regulated by temporal control of class I PI3K activity. Stimulation of tumor necrosis factor-alpha (TNF-alpha)-primed human neutrophils with N-formyl-methionyl-leucyl-phenylalanine (fMLP) results in biphasic activation of PI3K; the first phase is largely dependent on PI3Kgamma, and the second phase is largely dependent on PI3Kdelta. The second phase of PI3K activation requires the first phase; it is this second phase that is augmented by TNF-alpha priming and that regulates parallel activation of ROS production. Surprisingly, although TNF-alpha-primed mouse bone marrow-derived neutrophils exhibit superficially similar patterns of PI3K activation and ROS production in response to fMLP, these responses are substantially lower and largely dependent on PI3Kgamma alone. These results start to define which PI3K isoforms are responsible for modulating neutrophil responsiveness to infection and inflammation.

PI 3-kinase p110beta: a new target for antithrombotic therapy.[Pubmed:15834429]

Nat Med. 2005 May;11(5):507-14.

Platelet activation at sites of vascular injury is essential for the arrest of bleeding; however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances (high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(3) adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K p110beta as an important new target for antithrombotic therapy.

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110β catalytic subunit, used for cancer treatment.

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