6XRM

Crystal structure of human PI3K-gamma in complex with Compound 4

Summary for 6XRM

• Entry DOI: 10.2210/pdb6xrm/pdb
• Related: 6XRL
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one, SULFATE ION, ... (4 entities in total)
• Functional Keywords: phosphoinositide 3-kinase gamma, inhibitor, immunosuppression, cancer, proteros, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 109419.47

Authors

Walker, N.P.,Jeffrey, J.L. (deposition date: 2020-07-13, release date: 2020-09-16, Last modification date: 2024-03-06)

Primary citation

Drew, S.L.,Thomas-Tran, R.,Beatty, J.W.,Fournier, J.,Lawson, K.V.,Miles, D.H.,Mata, G.,Sharif, E.U.,Yan, X.,Mailyan, A.K.,Ginn, E.,Chen, J.,Wong, K.,Soni, D.,Dhanota, P.,Chen, P.Y.,Shaqfeh, S.G.,Meleza, C.,Pham, A.T.,Chen, A.,Zhao, X.,Banuelos, J.,Jin, L.,Schindler, U.,Walters, M.J.,Young, S.W.,Walker, N.P.,Leleti, M.R.,Powers, J.P.,Jeffrey, J.L.
Discovery of Potent and Selective PI3K gamma Inhibitors.
J.Med.Chem., 63:11235-11257, 2020

PubMed Abstract: The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of potent PI3Kγ inhibitors that attain high isoform selectivity through the divergent projection of substituents into both the "selectivity" and "alkyl-induced" pockets within the adenosine triphosphate (ATP) binding site of PI3Kγ. These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1-pyrazol-4-yl)pyrazolo[1,5-]pyrimidin-5-yl]-2-[(1)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1-isoindol-1-one (, IC = 0.064 μM, THP-1 cells), which displays >600-fold selectivity for PI3Kγ over the other class I isoforms and is a promising step toward the identification of a clinical development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater γ-selectivity can be achieved by inhibitors that occupy an "alkyl-induced" pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kγ.

PubMed: 32865410
DOI: 10.1021/acs.jmedchem.0c01203

Experimental method

X-RAY DIFFRACTION (2.88 Å)