4AOF

Selective small molecule inhibitor discovered by chemoproteomic assay platform reveals regulation of Th17 cell differentiation by PI3Kgamma

Summary for 4AOF

• Entry DOI: 10.2210/pdb4aof/pdb
• Related: 1E8Y 1E8Z 1HE8 2A4Z 2A5U 2CHW 2CHX 2CHZ 2V4L 3ZVV 3ZW3 4ANU 4ANV 4ANW 4ANX
• Descriptor: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM, N-[6-(5-methylsulfonylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]ethanamide (3 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P48736
• Total number of polymer chains: 1
• Total formula weight: 110229.55

Authors

Bergamini, G.,Bell, K.,Shimamura, S.,Werner, T.,Cansfield, A.,Muller, K.,Perrin, J.,Rau, C.,Ellard, K.,Hopf, C.,Doce, C.,Leggate, D.,Mangano, R.,Mathieson, T.,OMahony, A.,Plavec, I.,Rharbaoui, F.,Reinhard, F.,Savitski, M.M.,Ramsden, N.,Hirsch, E.,Drewes, G.,Rausch, O.,Bantscheff, M.,Neubauer, G. (deposition date: 2012-03-26, release date: 2012-05-09, Last modification date: 2023-12-20)

Primary citation

Bergamini, G.,Bell, K.,Shimamura, S.,Werner, T.,Cansfield, A.,Muller, K.,Perrin, J.,Rau, C.,Ellard, K.,Hopf, C.,Doce, C.,Leggate, D.,Mangano, R.,Mathieson, T.,O'Mahony, A.,Plavec, I.,Rharbaoui, F.,Reinhard, F.,Savitski, M.M.,Ramsden, N.,Hirsch, E.,Drewes, G.,Rausch, O.,Bantscheff, M.,Neubauer, G.
A Selective Inhibitor Reveals Pi3Kgamma Dependence of T(H)17 Cell Differentiation.
Nat.Chem.Biol., 8:576-, 2012

PubMed Abstract: We devised a high-throughput chemoproteomics method that enabled multiplexed screening of 16,000 compounds against native protein and lipid kinases in cell extracts. Optimization of one chemical series resulted in CZC24832, which is to our knowledge the first selective inhibitor of phosphoinositide 3-kinase γ (PI3Kγ) with efficacy in in vitro and in vivo models of inflammation. Extensive target- and cell-based profiling of CZC24832 revealed regulation of interleukin-17-producing T helper cell (T(H)17) differentiation by PI3Kγ, thus reinforcing selective inhibition of PI3Kγ as a potential treatment for inflammatory and autoimmune diseases.

PubMed: 22544264
DOI: 10.1038/NCHEMBIO.957

Experimental method

X-RAY DIFFRACTION (3.3 Å)