title: The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.
abstract: Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.
authors.affiliation: Medical Research Council-Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Berndt
authors.forename: Simon
authors.initials: S
authors.lastname: Miller
authors.forename: Olusegun
authors.initials: O
authors.lastname: Williams
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Le
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Houseman
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Pacold
authors.forename: Fabrice
authors.initials: F
authors.lastname: Gorrec
authors.forename: Wai-Ching
authors.initials: WC
authors.lastname: Hon
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
authors.forename: Pascale
authors.initials: P
authors.lastname: Gaillard
authors.forename: Thomas
authors.initials: T
authors.lastname: Rückle
authors.forename: Matthias K
authors.initials: MK
authors.lastname: Schwarz
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Shaw
authors.forename: Roger L
authors.initials: RL
authors.lastname: Williams
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D018411:Spodoptera; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases