7LM2

HUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 3C

Summary for 7LM2

• Entry DOI: 10.2210/pdb7lm2/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, cyclopropyl[(3S)-3-{[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]amino}pyrrolidin-1-yl]methanone, ... (6 entities in total)
• Functional Keywords: pi3kdelta kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 138292.01

Authors

Lesburg, C.A.,Augustin, M. (deposition date: 2021-02-05, release date: 2021-04-21, Last modification date: 2024-04-03)

Primary citation

Methot, J.L.,Zhou, H.,McGowan, M.A.,Anthony, N.J.,Christopher, M.,Garcia, Y.,Achab, A.,Lipford, K.,Trotter, B.W.,Altman, M.D.,Fradera, X.,Lesburg, C.A.,Li, C.,Alves, S.,Chappell, C.P.,Jain, R.,Mangado, R.,Pinheiro, E.,Williams, S.M.G.,Goldenblatt, P.,Hill, A.,Shaffer, L.,Chen, D.,Tong, V.,McLeod, R.L.,Lee, H.H.,Yu, H.,Shah, S.,Katz, J.D.
Projected Dose Optimization of Amino- and Hydroxypyrrolidine Purine PI3K delta Immunomodulators.
J.Med.Chem., 64:5137-5156, 2021

PubMed 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 (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 gave a dose-dependent reduction in pulmonary bronchoalveolar lavage inflammation eosinophil cell count.

PubMed: 33797901
DOI: 10.1021/acs.jmedchem.1c00237

Experimental method

X-RAY DIFFRACTION (2.79 Å)