5fi4: Difference between revisions

← Older edit

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 12: / Line 12: @@
 == Function ==
 [https://www.uniprot.org/uniprot/PK3CA_HUMAN PK3CA_HUMAN] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.<ref>PMID:21708979</ref>
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5'-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5'-alkoxy heteroaryl rings at the 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6'-Alkoxy 5'-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound 14 with 1,1,1-trifluoroisopropoxy group at 6'-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor-bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound 14 in PI3Kalpha, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop.
-Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model.,Han W, Menezes DL, Xu Y, Knapp MS, Elling R, Burger MT, Ni ZJ, Smith A, Lan J, Williams TE, Verhagen J, Huh K, Merritt H, Chan J, Kaufman S, Voliva CF, Pecchi S Bioorg Med Chem Lett. 2016 Feb 1;26(3):742-6. doi: 10.1016/j.bmcl.2016.01.003., Epub 2016 Jan 5. PMID:26774655<ref>PMID:26774655</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 5fi4" style="background-color:#fffaf0;"></div>
 ==See Also==