3rwp

Discovery of a Novel, Potent and Selective Inhibitor of 3-Phosphoinositide Dependent Kinase (PDK1)

spinqualitylabelsall models 3rwp, resolution 1.92Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3rwp is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.92Å Ligands: ABQ, GOL, SEP, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PDPK1_HUMAN Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive. Publication Abstract from PubMed Analogs substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrazin-2-yl-methano ne were discovered as potent and selective inhibitors of PDK1 with potential as anti-cancer agents. An early lead with 2-pyridine-3-yl-ethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kalpha through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and by substitution on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogs have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogs was assessed by the inhibition of AKT phosphorylation (T308) and by their anti-proliferation activity against a number of tumor cell lines. Discovery of Novel, Potent and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1).,Murphy ST, Bailey S, Burke BJ, Chappie TA, Ferre R, Greasley S, Hickey MJ, Humphrey J, Kablaoui N, Kath J, Kazmirski S, Kraus M, Kupchinskey S, Li J, Marx MA, Richter D, Tanis SP, Tran K, Vernier W, Alton G, Baxi SM, Ermolieff J, Lingardo L, Xie Z, Yin MJ, Yu XH J Med Chem. 2011 Oct 31. PMID:22040023 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Pdk1 3D structures

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