4ANW
Complexes of PI3Kgamma with isoform selective inhibitors.
Summary for 4ANW
| Entry DOI | 10.2210/pdb4anw/pdb |
| Related | 1E8Y 1E8Z 1HE8 2A4Z 2A5U 2CHW 2CHX 2CHZ 2V4L 3ZVV 3ZW3 4ANU 4ANV 4ANX |
| Descriptor | PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM, SULFATE ION, 3-AMINO-6-{4-CHLORO-3-[(2,3-DIFLUOROPHENYL)SULFAMOYL]PHENYL}-N-METHYLPYRAZINE-2-CARBOXAMIDE, ... (4 entities in total) |
| Functional Keywords | transferase |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 1 |
| Total formula weight | 112648.59 |
| Authors | Foster, P.G.,Lougheed, J.C. (deposition date: 2012-03-22, release date: 2012-05-09, Last modification date: 2024-05-01) |
| Primary citation | Leahy, J.W.,Buhr, C.A.,Johnson, H.W.B.,Kim, B.G.,Baik, T.,Cannoy, J.,Forsyth, T.P.,Jeong, J.W.,Lee, M.S.,Ma, S.,Noson, K.,Wang, L.,Williams, M.,Nuss, J.M.,Brooks, E.,Heald, N.,Holst, C.,Jaeger, C.,Lam, S.,Lougheed, J.C.,Nguyen, L.,Plonowski, A.,Stout, T.,Foster, P.G.,Wu, X.,Yakes, M.F.,Yu, R.,Zhang, W.,Lamb, P.,Raeber, O. The Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase Gamma Inhibitors J.Med.Chem., 55:5467-, 2012 Cited by PubMed Abstract: The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kγ revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability. PubMed: 22548342DOI: 10.1021/JM300403A PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.31 Å) |
Structure validation
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