Literature DB >> 28947940

Design of Selective Benzoxazepin PI3Kδ Inhibitors Through Control of Dihedral Angles.

Brian S Safina1, Richard L Elliott2, Andrew K Forrest2, Robert A Heald2, Jeremy M Murray1, Jim Nonomiya1, Jodie Pang1, Laurent Salphati1, Eileen M Seward2, Steven T Staben1, Mark Ultsch1, Binqing Wei1, Wenqian Yang3, Daniel P Sutherlin1.   

Abstract

A novel selective benzoxazepin inhibitor of PI3Kδ has been discovered. Beginning from compound 3, an αPI3K inhibitor, we utilized structure-based drug design and computational analysis of dihedral torsion angles to optimize for PI3Kδ isoform potency and isoform selectivity. Further medicinal chemistry optimization of the series led to the identification of 24, a highly potent and selective inhibitor of PI3Kδ.

Entities:  

Keywords:  PI3K delta inhibitor; PI3K isoform selectivity; ligand-based design

Year:  2017        PMID： 28947940      PMCID： PMC5601369          DOI： 10.1021/acsmedchemlett.7b00170

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  14 in total

1.  Potent and selective inhibitors of PI3Kδ: obtaining isoform selectivity from the affinity pocket and tryptophan shelf.

Authors:  Daniel P Sutherlin; Stewart Baker; Angelina Bisconte; Paul M Blaney; Anthony Brown; Bryan K Chan; David Chantry; Georgette Castanedo; Paul DePledge; Paul Goldsmith; David M Goldstein; Timothy Hancox; Jasmit Kaur; David Knowles; Rama Kondru; John Lesnick; Matthew C Lucas; Cristina Lewis; Jeremy Murray; Alan J Nadin; Jim Nonomiya; Jodie Pang; Neil Pegg; Steve Price; Karin Reif; Brian S Safina; Laurent Salphati; Steven Staben; Eileen M Seward; Stephen Shuttleworth; Sukhjit Sohal; Zachary K Sweeney; Mark Ultsch; Bohdan Waszkowycz; Binqing Wei
Journal:  Bioorg Med Chem Lett       Date:  2012-05-17       Impact factor: 2.823

Review 2.  Pharmacophore modeling and applications in drug discovery: challenges and recent advances.

Authors:  Sheng-Yong Yang
Journal:  Drug Discov Today       Date:  2010-04-01       Impact factor: 7.851

Review 3.  Exploiting the PI3K/AKT pathway for cancer drug discovery.

Authors:  Bryan T Hennessy; Debra L Smith; Prahlad T Ram; Yiling Lu; Gordon B Mills
Journal:  Nat Rev Drug Discov       Date:  2005-12       Impact factor: 84.694

Review 4.  Small molecule conformational preferences derived from crystal structure data. A medicinal chemistry focused analysis.

Authors:  Ken A Brameld; Bernd Kuhn; Deborah C Reuter; Martin Stahl
Journal:  J Chem Inf Model       Date:  2008-01-10       Impact factor: 4.956

Review 5.  PI3Kδ and PI3Kγ as targets for autoimmune and inflammatory diseases.

Authors:  Timothy D Cushing; Daniela P Metz; Douglas A Whittington; Lawrence R McGee
Journal:  J Med Chem       Date:  2012-09-13       Impact factor: 7.446

6.  A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design.

Authors:  Brett R Beno; Kap-Sun Yeung; Michael D Bartberger; Lewis D Pennington; Nicholas A Meanwell
Journal:  J Med Chem       Date:  2015-03-03       Impact factor: 7.446

7.  The Rational Design of Selective Benzoxazepin Inhibitors of the α-Isoform of Phosphoinositide 3-Kinase Culminating in the Identification of (S)-2-((2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326).

Authors:  Timothy P Heffron; Robert A Heald; Chudi Ndubaku; BinQing Wei; Martin Augistin; Steven Do; Kyle Edgar; Charles Eigenbrot; Lori Friedman; Emanuela Gancia; Philip S Jackson; Graham Jones; Aleksander Kolesnikov; Leslie B Lee; John D Lesnick; Cristina Lewis; Neville McLean; Mario Mörtl; Jim Nonomiya; Jodie Pang; Steve Price; Wei Wei Prior; Laurent Salphati; Steve Sideris; Steven T Staben; Stefan Steinbacher; Vickie Tsui; Jeffrey Wallin; Deepak Sampath; Alan G Olivero
Journal:  J Med Chem       Date:  2016-01-20       Impact factor: 7.446

8.  Identification of GNE-293, a potent and selective PI3Kδ inhibitor: navigating in vitro genotoxicity while improving potency and selectivity.

Authors:  Brian S Safina; Zachary K Sweeney; Jun Li; Bryan K Chan; Angelina Bisconte; Diane Carrera; Georgette Castanedo; Michael Flagella; Robert Heald; Cristina Lewis; Jeremy M Murray; Jim Nonomiya; Jodie Pang; Steve Price; Karin Reif; Laurent Salphati; Eileen M Seward; Binqing Wei; Daniel P Sutherlin
Journal:  Bioorg Med Chem Lett       Date:  2013-06-29       Impact factor: 2.823

9.  Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity.

Authors:  Chudi O Ndubaku; Timothy P Heffron; Steven T Staben; Matthew Baumgardner; Nicole Blaquiere; Erin Bradley; Richard Bull; Steven Do; Jennafer Dotson; Danette Dudley; Kyle A Edgar; Lori S Friedman; Richard Goldsmith; Robert A Heald; Aleksandr Kolesnikov; Leslie Lee; Cristina Lewis; Michelle Nannini; Jim Nonomiya; Jodie Pang; Steve Price; Wei Wei Prior; Laurent Salphati; Steve Sideris; Jeffery J Wallin; Lan Wang; BinQing Wei; Deepak Sampath; Alan G Olivero
Journal:  J Med Chem       Date:  2013-06-03       Impact factor: 7.446

10.  The Cambridge Structural Database.

Authors:  Colin R Groom; Ian J Bruno; Matthew P Lightfoot; Suzanna C Ward
Journal:  Acta Crystallogr B Struct Sci Cryst Eng Mater       Date:  2016-04-01
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  3 in total

1.  Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors.

Authors:  Zied Gaieb; Kaelin D Fleming; Manoj K Rathinaswamy; Chiara Borsari; Noah J Harris; Brandon E Moeller; Matthias P Wymann; Rommie E Amaro; John E Burke
Journal:  Elife       Date:  2021-03-04       Impact factor: 8.140

2.  New insights and innovation from a million crystal structures in the Cambridge Structural Database.

Authors:  Jason C Cole; Seth Wiggin; Francesca Stanzione
Journal:  Struct Dyn       Date:  2019-08-28       Impact factor: 2.920

3.  Structural Insights into the Interactions of Digoxin and Na+/K+-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation.

Authors:  Yulin Ren; Sijin Wu; Joanna E Burdette; Xiaolin Cheng; A Douglas Kinghorn
Journal:  Molecules       Date:  2021-06-16       Impact factor: 4.411
  3 in total

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