Literature DB >> 27660855

Discovery of Orally Efficacious Phosphoinositide 3-Kinase δ Inhibitors with Improved Metabolic Stability.

Leena Patel1, Jayaraman Chandrasekhar1, Jerry Evarts1, Kristen Forseth1, Aaron C Haran1, Carmen Ip1, Adam Kashishian1, Musong Kim1, David Koditek1, Sandy Koppenol1, Latesh Lad1, Eve-Irene Lepist1, Mary E McGrath1, Stephane Perreault1, Kamal D Puri1, Armando G Villaseñor1, John R Somoza1, Bart H Steiner1, Joseph Therrien1, Jennifer Treiberg1, Gary Phillips1.   

Abstract

Aberrant signaling of phosphoinositide 3-kinase δ (PI3Kδ) has been implicated in numerous pathologies including hematological malignancies and rheumatoid arthritis. Described in this manuscript are the discovery, optimization, and in vivo evaluation of a novel series of pyridine-containing PI3Kδ inhibitors. This work led to the discovery of 35, a highly selective inhibitor of PI3Kδ which displays an excellent pharmacokinetic profile and is efficacious in a rodent model of rheumatoid arthritis.

Entities:  

Year:  2016        PMID： 27660855     DOI： 10.1021/acs.jmedchem.6b01169

Source DB:  PubMed          Journal:  J Med Chem        ISSN： 0022-2623            Impact factor:   7.446


  7 in total

1.  Targeting PI3Kδ function for amelioration of murine chronic graft-versus-host disease.

Authors:  Katelyn Paz; Ryan Flynn; Jing Du; Stacey Tannheimer; Amy J Johnson; Shuai Dong; Anne-Katrien Stark; Klaus Okkenhaug; Angela Panoskaltsis-Mortari; Peter T Sage; Arlene H Sharpe; Leo Luznik; Jerome Ritz; Robert J Soiffer; Corey S Cutler; John Koreth; Joseph H Antin; David B Miklos; Kelli P MacDonald; Geoffrey R Hill; Ivan Maillard; Jonathan S Serody; William J Murphy; David H Munn; Colby Feser; Michael Zaiken; Bart Vanhaesebroeck; Laurence A Turka; John C Byrd; Bruce R Blazar
Journal:  Am J Transplant       Date:  2019-03-19       Impact factor: 8.086

2.  Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors.

Authors:  Klemens Hoegenauer; Nicolas Soldermann; Frédéric Zécri; Ross S Strang; Nadege Graveleau; Romain M Wolf; Nigel G Cooke; Alexander B Smith; Gregory J Hollingworth; Joachim Blanz; Sascha Gutmann; Gabriele Rummel; Amanda Littlewood-Evans; Christoph Burkhart
Journal:  ACS Med Chem Lett       Date:  2017-08-25       Impact factor: 4.345

3.  Discovery of an Atropisomeric PI3Kβ Selective Inhibitor through Optimization of the Hinge Binding Motif.

Authors:  Stephane Perreault; Fatima Arjmand; Jayaraman Chandrasekhar; Jia Hao; Kathleen S Keegan; David Koditek; Eve-Irene Lepist; Clinton K Matson; Mary E McGrath; Leena Patel; Kassandra Sedillo; Joseph Therrien; Nicholas A Till; Adrian Tomkinson; Jennifer Treiberg; Yelena Zherebina; Gary Phillips
Journal:  ACS Med Chem Lett       Date:  2020-04-13       Impact factor: 4.345

4.  IGF1R as druggable target mediating PI3K-δ inhibitor resistance in a murine model of chronic lymphocytic leukemia.

Authors:  Annika Scheffold; Billy Michael Chelliah Jebaraj; Eugen Tausch; Johannes Bloehdorn; Paolo Ghia; Anella Yahiaoui; Anna Dolnik; Tamara Jacqueline Blätte; Lars Bullinger; Rashmi Priyadharshini Dheenadayalan; Li Li; Christof Schneider; Shih-Shih Chen; Nicholas Chiorazzi; Sascha Dietrich; Martina Seiffert; Stacey Tannheimer; Hartmut Döhner; Daniel Mertens; Stephan Stilgenbauer
Journal:  Blood       Date:  2019-04-22       Impact factor: 22.113

5.  Design, Synthesis, and Biological Evaluation of Quinazolin-4-one-Based Hydroxamic Acids as Dual PI3K/HDAC Inhibitors.

Authors:  Ashish Thakur; Gregory J Tawa; Mark J Henderson; Carina Danchik; Suiyang Liu; Pranav Shah; Amy Q Wang; Garrett Dunn; Md Kabir; Elias C Padilha; Xin Xu; Anton Simeonov; Surender Kharbanda; Richard Stone; Gurmit Grewal
Journal:  J Med Chem       Date:  2020-04-08       Impact factor: 7.446

6.  PI3Kδ inhibitor idelalisib in combination with BTK inhibitor ONO/GS-4059 in diffuse large B cell lymphoma with acquired resistance to PI3Kδ and BTK inhibitors.

Authors:  Anella Yahiaoui; Sarah A Meadows; Rick A Sorensen; Zhi-Hua Cui; Kathleen S Keegan; Robert Brockett; Guang Chen; Christophe Quéva; Li Li; Stacey L Tannheimer
Journal:  PLoS One       Date:  2017-02-08       Impact factor: 3.240

7.  The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL.

Authors:  Etai Adam; Hye Na Kim; Eun Ji Gang; Caitlin Schnair; Solomon Lee; Solah Lee; Sajad Khazal; Osanna Kosoyan; Marina Konopleva; Chintan Parekh; Deepa Bhojwani; Alan S Wayne; Hisham Abdel-Azim; Nora Heisterkamp; Yong-Mi Kim
Journal:  Cancers (Basel)       Date:  2017-09-10       Impact factor: 6.639
  7 in total

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