8BCY

HUMAN PI3KDELTA IN COMPLEX WITH COMPOUND 13

Summary for 8BCY

• Entry DOI: 10.2210/pdb8bcy/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 9-[2-(3,4-dichlorophenyl)ethyl]-2-(3-hydroxyphenyl)-8-oxidanylidene-7~{H}-purine-6-carboxamide, ... (4 entities in total)
• Functional Keywords: pi3kdelta kinase, pi3kdelta kinase inhibitor, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 137924.46

Authors

Pala, D.,Mazzucato, R.,Capelli, A.M.,Rancati, F.,Biagetti, M. (deposition date: 2022-10-17, release date: 2023-05-10, Last modification date: 2024-06-19)

Primary citation

Mazzucato, R.,Roberti, M.,Capelli, A.M.,Rancati, F.,Biagetti, M.,Fiorelli, C.,Bruno, P.,Ronchi, P.,Bertolini, S.,Corsi, M.,Pala, D.
Application of an "inhalation by design" approach to the identification and in-vitro evaluation of novel purine based PI3K delta inhibitors.
Eur.J.Med.Chem., 254:115331-115331, 2023

PubMed Abstract: PI3Kδ is a lipid kinase which plays a key role in airway inflammatory conditions. Accordingly, the inhibition of PI3Kδ can be considered a valuable strategy for the treatment of chronic respiratory diseases such as Asthma and Chronic obstructive pulmonary disease (COPD). In this work, we describe our efforts to identify new PI3Kδ inhibitors following an "inhalation by design" strategy. Starting from the identification of a purine scaffold, we carried out a preliminary SAR expansion which led to the identification of a new hit characterized by a high enzymatic potency and moderate PI3Kδ selectivity. A subsequent optimization led to novel purine based derivatives with favorable in vitro ADME profiles, which might represent promising starting points for future development of new inhaled drug candidates.

PubMed: 37094451
DOI: 10.1016/j.ejmech.2023.115331

Experimental method

X-RAY DIFFRACTION (2.43 Å)