6EYZ

PI3 kinase delta in complex with 4-Fluorophenyl 5-(4-(5-((4-isopropylpiperazin-1-yl)methyl)oxazol-2-yl)-1H-indazol-6-yl)-2-methoxynicotinate

Summary for 6EYZ

• Entry DOI: 10.2210/pdb6eyz/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, 2-methoxy-5-[4-[5-[(4-propan-2-ylpiperazin-1-yl)methyl]-1,3-oxazol-2-yl]-2~{H}-indazol-6-yl]pyridine-3-carboxylic acid (3 entities in total)
• Functional Keywords: covalent inhibitor, kinase, drug discovery, complex, transferase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 121327.88

Authors

Convery, M.A.,Campos, S.,Dalton, S.E. (deposition date: 2017-11-13, release date: 2017-12-20, Last modification date: 2024-11-13)

Primary citation

Dalton, S.E.,Dittus, L.,Thomas, D.A.,Convery, M.A.,Nunes, J.,Bush, J.T.,Evans, J.P.,Werner, T.,Bantscheff, M.,Murphy, J.A.,Campos, S.
Selectively Targeting the Kinome-Conserved Lysine of PI3K delta as a General Approach to Covalent Kinase Inhibition.
J. Am. Chem. Soc., 140:932-939, 2018

PubMed Abstract: Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is limited to ∼200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kδ inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer a general strategy, as an alternative to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors.

PubMed: 29232121
DOI: 10.1021/jacs.7b08979

Experimental method

X-RAY DIFFRACTION (2.2 Å)