5M6U

HUMAN PI3KDELTA IN COMPLEX WITH LASW1579

Summary for 5M6U

• Entry DOI: 10.2210/pdb5m6u/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 4-azanyl-6-[[(1~{S})-1-(4-oxidanylidene-3-phenyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino]pyrimidine-5-carbonitrile (3 entities in total)
• Functional Keywords: pi3kdelta kinase, proteros biostructures gmbh, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 199769.15

Authors

Segarra, V.,Hernandez, B.,Lozoya, E.,Blaesse, M.,Hoeppner, S.,Jestel, A. (deposition date: 2016-10-26, release date: 2017-02-01, Last modification date: 2024-01-17)

Primary citation

Erra, M.,Taltavull, J.,Greco, A.,Bernal, F.J.,Caturla, J.F.,Gracia, J.,Dominguez, M.,Sabate, M.,Paris, S.,Soria, S.,Hernandez, B.,Armengol, C.,Cabedo, J.,Bravo, M.,Calama, E.,Miralpeix, M.,Lehner, M.D.
Discovery of a Potent, Selective, and Orally Available PI3K delta Inhibitor for the Treatment of Inflammatory Diseases.
ACS Med Chem Lett, 8:118-123, 2017

PubMed Abstract: The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans. Structure-activity relationships and structure-property relationships are discussed. This medicinal chemistry exercise led to the identification of LAS191954 as a candidate for clinical development.

PubMed: 28105286
DOI: 10.1021/acsmedchemlett.6b00438

Experimental method

X-RAY DIFFRACTION (2.85 Å)