Discovery of Potent and Selective PI3Kγ Inhibitors
| العنوان: | Discovery of Potent and Selective PI3Kγ Inhibitors |
|---|---|
| المؤلفون: | Dillon H. Miles, Ada Chen, Manmohan Reddy Leleti, Divyank Soni, Stephen W Young, Artur K. Mailyan, Kenneth V. Lawson, Stefan G Shaqfeh, Ehesan U. Sharif, Pei-Yu Chen, Jenna L. Jeffrey, Jesus Banuelos, Xuelei Yan, Samuel L Drew, Nigel Walker, Puja Dhanota, Lixia Jin, Jay P. Powers, Elaine Ginn, Guillaume Mata, Kent Wong, Jeremy Fournier, Joel W. Beatty, Rhiannon Thomas-Tran, Ulrike Schindler, Amber Pham, Matthew J. Walters, Jie Chen, Cesar Meleza, Xiaoning Zhao |
| المصدر: | Journal of Medicinal Chemistry. 63:11235-11257 |
| بيانات النشر: | American Chemical Society (ACS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Gene isoform, Stereochemistry, Crystallography, X-Ray, 01 natural sciences, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, Animals, Class Ib Phosphatidylinositol 3-Kinase, Humans, Binding site, Phosphoinositide-3 Kinase Inhibitors, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Trifluoromethyl, Bicyclic molecule, Lipid signaling, Rats, 0104 chemical sciences, Molecular Docking Simulation, 010404 medicinal & biomolecular chemistry, Enzyme, chemistry, Drug Design, Molecular Medicine, Selectivity, Adenosine triphosphate |
| الوصف: | 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-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4, IC50 = 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. |
| تدمد: | 1520-4804 0022-2623 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::237c477c3969b94ce636dfc76aca3e4fTest https://doi.org/10.1021/acs.jmedchem.0c01203Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....237c477c3969b94ce636dfc76aca3e4f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
|---|