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The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors

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Berndt, Alex, Miller, Simon, Williams, Olusegun, Le, Daniel D, Houseman, Benjamin T, Pacold, Joseph I, Gorrec, Fabrice, Hon, Wai-Ching, Ren, Pingda, Liu, Yi, Rommel, Christian, Gaillard, Pascale, Rückle, Thomas, Schwarz, Matthias K, Shokat, Kevan M, Shaw, Jeffrey P, Williams, Roger L·2010·Nature Chemical Biology
DOI 10.1038/nchembio.293
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Abstract

Deregulation of the phosphoinositide 3-kinase (PI3K) pathway has been implicated in numerous pathologies like cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small molecule and ATP-competitive PI3K inhibitors with a wide range of selectivities have entered clinical development. In order to understand mechanisms underlying isoform selectivity of these inhibitors, we developed a novel expression strategy that enabled us to determine the first crystal structure of the catalytic subunit of the class IA PI3K p110δ. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI3K inhibitors reveal that selectivity towards p110δ 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 p110δ with greatly improved potencies.

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Metadata

Authors
Berndt, A., Miller, S., Williams, O., Le, D. D., Houseman, B. T., Pacold, J. I., Gorrec, F., Hon, W.-C., Ren, P., Liu, Y., Rommel, C., Gaillard, P., Rückle, T., Schwarz, M. K., Shokat, K. M., Shaw, J. P., & Williams, R. L.
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2010-01-10
Volume
6
Issue
2
Pages
117-124
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
DOI
10.1038/nchembio.293
OpenAlex
W2127355894
Cited by
292
References
3
FWCI
10.04
Type
journal article
Language
en
Update notices
erratum (2010-03-01)
Open access
green
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CoChat. (2026). Citation check: The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. https://app.cochat.ai/papers/10.1038/nchembio.293
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Berndt, A., Miller, S., Williams, O., Le, D. D., Houseman, B. T., Pacold, J. I., Gorrec, F., Hon, W.-C., Ren, P., Liu, Y., Rommel, C., Gaillard, P., Rückle, T., Schwarz, M. K., Shokat, K. M., Shaw, J. P., & Williams, R. L. (2010). The p110δ structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nature Chemical Biology. https://doi.org/10.1038/nchembio.293

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