Literature DB >> 27660692

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate.

Catherine A Evans1, Tao Liu1, André Lescarbeau1, Somarajan J Nair1, Louis Grenier1, Johan A Pradeilles1, Quentin Glenadel1, Thomas Tibbitts1, Ann M Rowley1, Jonathan P DiNitto1, Erin E Brophy1, Erin L O'Hearn1, Janid A Ali1, David G Winkler1, Stanley I Goldstein1, Patrick O'Hearn1, Christian M Martin1, Jennifer G Hoyt1, John R Soglia1, Culver Cheung1, Melissa M Pink1, Jennifer L Proctor1, Vito J Palombella1, Martin R Tremblay1, Alfredo C Castro1.   

Abstract

Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.

Entities:  

Keywords:  IPI-549; PI3K-gamma inhibitor; immuno-oncology; isoform selectivity; neutrophil migration; phosphoinositide-3-kinase

Year:  2016        PMID： 27660692      PMCID： PMC5018865          DOI： 10.1021/acsmedchemlett.6b00238

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


  26 in total

1.  Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration.

Authors:  T Sasaki; J Irie-Sasaki; R G Jones; A J Oliveira-dos-Santos; W L Stanford; B Bolon; A Wakeham; A Itie; D Bouchard; I Kozieradzki; N Joza; T W Mak; P S Ohashi; A Suzuki; J M Penninger
Journal:  Science       Date:  2000-02-11       Impact factor: 47.728

Review 2.  Molecules in medicine mini-review: isoforms of PI3K in biology and disease.

Authors:  Bart Vanhaesebroeck; Maria A Whitehead; Roberto Piñeiro
Journal:  J Mol Med (Berl)       Date:  2015-12-10       Impact factor: 4.599

Review 3.  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

4.  Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression.

Authors:  Michael C Schmid; Christie J Avraamides; Holly C Dippold; Irene Franco; Philippe Foubert; Lesley G Ellies; Lissette M Acevedo; Joan R E Manglicmot; Xiaodan Song; Wolfgang Wrasidlo; Sara L Blair; Mark H Ginsberg; David A Cheresh; Emilio Hirsch; Seth J Field; Judith A Varner
Journal:  Cancer Cell       Date:  2011-06-14       Impact factor: 31.743

5.  Discovery of Highly Isoform Selective Thiazolopiperidine Inhibitors of Phosphoinositide 3-Kinase γ.

Authors:  Philip N Collier; David Messersmith; Arnaud Le Tiran; Upul K Bandarage; Christina Boucher; Jon Come; Kevin M Cottrell; Veronique Damagnez; John D Doran; James P Griffith; Suvarna Khare-Pandit; Elaine B Krueger; Mark W Ledeboer; Brian Ledford; Yusheng Liao; Sudipta Mahajan; Cameron S Moody; Setu Roday; Tiansheng Wang; Jinwang Xu; Alex M Aronov
Journal:  J Med Chem       Date:  2015-07-06       Impact factor: 7.446

Review 6.  PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting.

Authors:  Lauren M Thorpe; Haluk Yuzugullu; Jean J Zhao
Journal:  Nat Rev Cancer       Date:  2015-01       Impact factor: 60.716

7.  Cutting edge: differential roles for phosphoinositide 3-kinases, p110gamma and p110delta, in lymphocyte chemotaxis and homing.

Authors:  Karin Reif; Klaus Okkenhaug; Takehiko Sasaki; Joseph M Penninger; Bart Vanhaesebroeck; Jason G Cyster
Journal:  J Immunol       Date:  2004-08-15       Impact factor: 5.422

8.  Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation.

Authors:  E Hirsch; V L Katanaev; C Garlanda; O Azzolino; L Pirola; L Silengo; S Sozzani; A Mantovani; F Altruda; M P Wymann
Journal:  Science       Date:  2000-02-11       Impact factor: 47.728

9.  A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.

Authors:  Zachary A Knight; Beatriz Gonzalez; Morri E Feldman; Eli R Zunder; David D Goldenberg; Olusegun Williams; Robbie Loewith; David Stokoe; Andras Balla; Balazs Toth; Tamas Balla; William A Weiss; Roger L Williams; Kevan M Shokat
Journal:  Cell       Date:  2006-04-27       Impact factor: 41.582

Review 10.  PI3K signalling in inflammation.

Authors:  P T Hawkins; L R Stephens
Journal:  Biochim Biophys Acta       Date:  2014-12-13
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  29 in total

Review 1.  Macrophages: The Road Less Traveled, Changing Anticancer Therapy.

Authors:  Jennifer L Guerriero
Journal:  Trends Mol Med       Date:  2018-04-11       Impact factor: 11.951

2.  Phosphoinositide-3-Kinase γ Is Not a Predominant Regulator of ATP-Dependent Directed Microglial Process Motility or Experience-Dependent Ocular Dominance Plasticity.

Authors:  Brendan S Whitelaw; Evelyn K Matei; Ania K Majewska
Journal:  eNeuro       Date:  2020-10-16

Review 3.  Kinase inhibitors: the road ahead.

Authors:  Fleur M Ferguson; Nathanael S Gray
Journal:  Nat Rev Drug Discov       Date:  2018-03-16       Impact factor: 84.694

4.  Small GTPase Rab8a-recruited Phosphatidylinositol 3-Kinase γ Regulates Signaling and Cytokine Outputs from Endosomal Toll-like Receptors.

Authors:  Adam A Wall; Lin Luo; Yu Hung; Samuel J Tong; Nicholas D Condon; Antje Blumenthal; Matthew J Sweet; Jennifer L Stow
Journal:  J Biol Chem       Date:  2017-01-27       Impact factor: 5.157

5.  Inhibition of the α-Subunit of Phosphoinositide 3-Kinase in Heart Increases Late Sodium Current and Is Arrhythmogenic.

Authors:  Tao Yang; David F Meoli; Javid Moslehi; Dan M Roden
Journal:  J Pharmacol Exp Ther       Date:  2018-03-21       Impact factor: 4.030

6.  Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells.

Authors:  Olivier De Henau; Matthew Rausch; David Winkler; Luis Felipe Campesato; Cailian Liu; Daniel Hirschhorn Cymerman; Sadna Budhu; Arnab Ghosh; Melissa Pink; Jeremy Tchaicha; Mark Douglas; Thomas Tibbitts; Sujata Sharma; Jennifer Proctor; Nicole Kosmider; Kerry White; Howard Stern; John Soglia; Julian Adams; Vito J Palombella; Karen McGovern; Jeffery L Kutok; Jedd D Wolchok; Taha Merghoub
Journal:  Nature       Date:  2016-11-09       Impact factor: 49.962

7.  PI3Kγ is a molecular switch that controls immune suppression.

Authors:  Megan M Kaneda; Karen S Messer; Natacha Ralainirina; Hongying Li; Christopher J Leem; Sara Gorjestani; Gyunghwi Woo; Abraham V Nguyen; Camila C Figueiredo; Philippe Foubert; Michael C Schmid; Melissa Pink; David G Winkler; Matthew Rausch; Vito J Palombella; Jeffery Kutok; Karen McGovern; Kelly A Frazer; Xuefeng Wu; Michael Karin; Roman Sasik; Ezra E W Cohen; Judith A Varner
Journal:  Nature       Date:  2016-09-19       Impact factor: 49.962

8.  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

9.  Discovery of a Novel Series of Potent and Selective Alkynylthiazole-Derived PI3Kγ Inhibitors.

Authors:  Upul K Bandarage; Alex M Aronov; Jingrong Cao; Jon H Come; Kevin M Cottrell; Robert J Davies; Simon Giroux; Marc Jacobs; Sudipta Mahajan; David Messersmith; Cameron S Moody; Rebecca Swett; Jinwang Xu
Journal:  ACS Med Chem Lett       Date:  2020-12-18       Impact factor: 4.345

Review 10.  The therapeutic implications of immunosuppressive tumor aerobic glycolysis.

Authors:  Bradley I Reinfeld; W Kimryn Rathmell; Tae Kon Kim; Jeffrey C Rathmell
Journal:  Cell Mol Immunol       Date:  2021-07-08       Impact factor: 11.530
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