PDBsum entry 7lm2

Transferase/transferase inhibitor

PDB id: 7lm2

Contents

Protein chains

935 a.a.

169 a.a.

Ligands

Y5Y

EDO

SO4

Waters ×8

PDB id:

7lm2

Name:

Transferase/transferase inhibitor

Title:

Human pi3kdelta in complex with compound 3c

Structure:

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform. Chain: a. Fragment: pi3-kinase p110 delta and p85 fragment. Synonym: ptdins-3-kinase subunit delta,phosphatidylinositol 4,5- bisphosphate 3-kinase 110 kda catalytic subunit delta,p110delta. Engineered: yes. Phosphatidylinositol 3-kinase regulatory subunit alpha. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pik3cd. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: pik3r1, grb1. Expression_system_taxid: 7108

Resolution:

2.79Å R-factor: 0.242 R-free: 0.290

Authors:

C.A.Lesburg,M.Augustin

Key ref:

J.L.Methot et al. (2021). Projected Dose Optimization of Amino- and Hydroxypyrrolidine Purine PI3Kδ Immunomodulators. J Med Chem, 64, 5137-5156. PubMed id: 33797901 DOI: 10.1021/acs.jmedchem.1c00237

Date:

05-Feb-21 Release date: 21-Apr-21

Protein chain

O00329  (PK3CD_HUMAN) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform from Homo sapiens

Seq: 1044 a.a.

Struc: 935 a.a.

Protein chain

P27986  (P85A_HUMAN) -  Phosphatidylinositol 3-kinase regulatory subunit alpha from Homo sapiens

Seq: 724 a.a.

Struc: 169 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: Chain A: E.C.2.7.1.137 - phosphatidylinositol 3-kinase.
• Pathway: 1-Phosphatidyl-myo-inositol Metabolism
• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl- sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H⁺
• Enzyme class 3: Chain A: E.C.2.7.1.153 - phosphatidylinositol-4,5-bisphosphate 3-kinase.

Pathway:

• Reaction: a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5- trisphosphate) + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.jmedchem.1c00237

J Med Chem 64:5137-5156 (2021)

PubMed id: 33797901

Projected Dose Optimization of Amino- and Hydroxypyrrolidine Purine PI3Kδ Immunomodulators.

J.L.Methot, H.Zhou, M.A.McGowan, N.J.Anthony, M.Christopher, Y.Garcia, A.Achab, K.Lipford, B.W.Trotter, M.D.Altman, X.Fradera, C.A.Lesburg, C.Li, S.Alves, C.P.Chappell, R.Jain, R.Mangado, E.Pinheiro, S.M.G.Williams, P.Goldenblatt, A.Hill, L.Shaffer, D.Chen, V.Tong, R.L.McLeod, H.H.Lee, H.Yu, S.Shah, J.D.Katz.

ABSTRACT

The approvals of idelalisib and duvelisib have validated PI3Kδ inhibitors for the treatment for hematological malignancies driven by the PI3K/AKT pathway. Our program led to the identification of structurally distinct heterocycloalkyl purine inhibitors with excellent isoform and kinome selectivity; however, they had high projected human doses. Improved ligand contacts gave potency enhancements, while replacement of metabolic liabilities led to extended half-lives in preclinical species, affording PI3Kδ inhibitors with low once-daily predicted human doses. Treatment of C57BL/6-Foxp3-GDL reporter mice with 30 and 100 mg/kg/day of 3c (MSD-496486311) led to a 70% reduction in Foxp3-expressing regulatory T cells as observed through bioluminescence imaging with luciferin, consistent with the role of PI3K/AKT signaling in Treg cell proliferation. As a model for allergic rhinitis and asthma, treatment of ovalbumin-challenged Brown Norway rats with 0.3 to 30 mg/kg/day of 3c gave a dose-dependent reduction in pulmonary bronchoalveolar lavage inflammation eosinophil cell count.