6ZAD

PI3K Delta in complex with methoxymethyloxathiatetraazatetracyclodocosahexaenedione

Summary for 6ZAD

• Entry DOI: 10.2210/pdb6zad/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, methoxymethyloxathiatetraazatetracyclodocosahexaenedione (3 entities in total)
• Functional Keywords: macrocycle, pi3k delta, thermodynamics, transferase
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 108214.12

Authors

Convery, M.A.,Hardy, C.J.,Spencer, J.A.,Rowland, P. (deposition date: 2020-06-05, release date: 2020-07-29, Last modification date: 2024-06-19)

Primary citation

Spencer, J.A.,Baldwin, I.R.,Barton, N.,Chung, C.W.,Convery, M.A.,Edwards, C.D.,Jamieson, C.,Mallett, D.N.,Rowedder, J.E.,Rowland, P.,Thomas, D.A.,Hardy, C.J.
Design and Development of a Macrocyclic Series Targeting Phosphoinositide 3-Kinase delta.
Acs Med.Chem.Lett., 11:1386-1391, 2020

PubMed Abstract: A macrocyclization approach has been explored on a series of benzoxazine phosphoinositide 3-kinase δ inhibitors, resulting in compounds with improved potency, permeability, and clearance while maintaining good solubility. The thermodynamics of binding was explored via surface plasmon resonance, and the binding of lead macrocycle was found to be almost exclusively entropically driven compared with progenitor , which demonstrated both enthalpic and entropic contributions. The pharmacokinetics of macrocycle was also explored , where it showed reduced clearance when compared with the progenitor . This work adds to the growing body of evidence that macrocyclization could provide an alternative and complementary approach to the design of small-molecule inhibitors, with the potential to deliver differentiated properties.

PubMed: 32676144
DOI: 10.1021/acsmedchemlett.0c00061

Experimental method

X-RAY DIFFRACTION (2.24 Å)