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Literature DB >> 32551006

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

Stephane Perreault¹, Fatima Arjmand², Jayaraman Chandrasekhar¹, Jia Hao¹, Kathleen S Keegan¹, David Koditek², Eve-Irene Lepist¹, Clinton K Matson¹, Mary E McGrath², Leena Patel¹, Kassandra Sedillo¹, Joseph Therrien¹, Nicholas A Till¹, Adrian Tomkinson², Jennifer Treiberg¹, Yelena Zherebina², Gary Phillips¹.

Abstract

A series of PI3Kβ selective inhibitors derived from a novel 4-(1H-benzo[d]imidazol-1-yl)quinoline chemotype has been rationally designed. Crucial to achieving the desired selectivity over the other class I PI3K isoforms, including the challenging δ-isoform, was the identification of a subset of substituted pyridine hinge binders. This work led to the discovery of (P)-14, a highly selective and orally bioavailable PI3Kβ inhibitor displaying an excellent pharmacokinetic profile in addition to great cellular potency in various PTEN-deficient tumor cell lines. Results from a dog toxicology study revealing structure-related, off-target ocular toxicity are also briefly discussed.

Entities: Chemical Disease Species

Year: 2020 PMID： 32551006 PMCID： PMC7294712 DOI： 10.1021/acsmedchemlett.0c00095

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

23 in total

1. Aldehyde oxidase: an enzyme of emerging importance in drug discovery.

Authors: David C Pryde; Deepak Dalvie; Qiyue Hu; Peter Jones; R Scott Obach; Thien-Duc Tran
Journal: J Med Chem Date: 2010-09-20 Impact factor: 7.446

Review 2. Assessing atropisomer axial chirality in drug discovery and development.

Authors: Steven R Laplante; Lee D Fader; Keith R Fandrick; Daniel R Fandrick; Oliver Hucke; Ray Kemper; Stephen P F Miller; Paul J Edwards
Journal: J Med Chem Date: 2011-09-15 Impact factor: 7.446

3. Synthesis and structure-activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors.

Authors: Hong Lin; Karl Erhard; Mary Ann Hardwicke; Juan I Luengo; James F Mack; Jeanelle McSurdy-Freed; Ramona Plant; Kaushik Raha; Cynthia M Rominger; Robert M Sanchez; Michael D Schaber; Mark J Schulz; Michael D Spengler; Rosanna Tedesco; Ren Xie; Jin J Zeng; Ralph A Rivero
Journal: Bioorg Med Chem Lett Date: 2012-02-04 Impact factor: 2.823

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

Authors: Leena Patel; Jayaraman Chandrasekhar; Jerry Evarts; Kristen Forseth; Aaron C Haran; Carmen Ip; Adam Kashishian; Musong Kim; David Koditek; Sandy Koppenol; Latesh Lad; Eve-Irene Lepist; Mary E McGrath; Stephane Perreault; Kamal D Puri; Armando G Villaseñor; John R Somoza; Bart H Steiner; Joseph Therrien; Jennifer Treiberg; Gary Phillips
Journal: J Med Chem Date: 2016-10-03 Impact factor: 7.446

5. Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery.

Authors: Nenad Manevski; Lloyd King; William R Pitt; Fabien Lecomte; Francesca Toselli
Journal: J Med Chem Date: 2019-08-20 Impact factor: 7.446

Review 6. Targeting the PI3K pathway in cancer: are we making headway?

Authors: Filip Janku; Timothy A Yap; Funda Meric-Bernstam
Journal: Nat Rev Clin Oncol Date: 2018-03-06 Impact factor: 66.675

Review 7. PI3K and cancer: lessons, challenges and opportunities.

Authors: David A Fruman; Christian Rommel
Journal: Nat Rev Drug Discov Date: 2014-02 Impact factor: 84.694

8. Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3Kβ and PI3Kδ for the treatment of PTEN-deficient cancers.

Authors: Bernard Barlaam; Sabina Cosulich; Sébastien Degorce; Martina Fitzek; Stephen Green; Urs Hancox; Christine Lambert-van der Brempt; Jean-Jacques Lohmann; Mickaël Maudet; Rémy Morgentin; Marie-Jeanne Pasquet; Aurélien Péru; Patrick Plé; Twana Saleh; Michel Vautier; Mike Walker; Lara Ward; Nicolas Warin
Journal: J Med Chem Date: 2015-01-07 Impact factor: 7.446

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

1. Aldehyde oxidase: an enzyme of emerging importance in drug discovery.

Review 2. Assessing atropisomer axial chirality in drug discovery and development.

3. Synthesis and structure-activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors.

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

5. Metabolism by Aldehyde Oxidase: Drug Design and Complementary Approaches to Challenges in Drug Discovery.

Review 6. Targeting the PI3K pathway in cancer: are we making headway?

Review 7. PI3K and cancer: lessons, challenges and opportunities.

8. Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3Kβ and PI3Kδ for the treatment of PTEN-deficient cancers.

9. Isoform-specific phosphoinositide 3-kinase inhibitors from an arylmorpholine scaffold.

Review 10. Structural comparisons of class I phosphoinositide 3-kinases.

1. Atropisomerism in the Pharmaceutically Relevant Realm.

2. Atropisomeric Racemization Kinetics of MRTX1719 Using Chiral Solvating Agent-Assisted ¹⁹F NMR Spectroscopy.