Discovery of a new series of PI3K-δ inhibitors from Virtual Screening

Xavier Fradera; Qiaolin Deng; Abdelganhi Achab; Yudith Garcia; Solomon D Kattar; Meredeth A McGowan; Joey L Methot; Kevin Wilson; Hua Zhou; Lynsey Shaffer; Peter Goldenblatt; Vincent Tong; Martin A Augustin; Michael D Altman; Charles A Lesburg; Sanjiv Shah; Jason D Katz

doi:10.1016/j.bmcl.2021.128046

Discovery of a new series of PI3K-δ inhibitors from Virtual Screening

Bioorg Med Chem Lett. 2021 Jun 15:42:128046. doi: 10.1016/j.bmcl.2021.128046. Epub 2021 Apr 16.

Authors

Xavier Fradera¹, Qiaolin Deng², Abdelganhi Achab³, Yudith Garcia³, Solomon D Kattar³, Meredeth A McGowan³, Joey L Methot³, Kevin Wilson³, Hua Zhou³, Lynsey Shaffer⁴, Peter Goldenblatt⁴, Vincent Tong⁵, Martin A Augustin⁶, Michael D Altman⁷, Charles A Lesburg⁷, Sanjiv Shah⁴, Jason D Katz³

Affiliations

¹ Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA, USA. Electronic address: xavier.fradera@merck.com.
² Computational and Structural Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA.
³ Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.
⁴ Quantitative Biosciences, Merck & Co., Inc., Boston, MA, USA.
⁵ PPDM, Merck & Co., Inc., Boston, MA, USA.
⁶ Proteros Biostructures GmbH, Martinsried, Germany.
⁷ Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA, USA.

PMID: 33865969
DOI: 10.1016/j.bmcl.2021.128046

Abstract

PI3K-δ mediates key immune cell signaling pathways and is a target of interest for treatment of oncological and immunological disorders. Here we describe the discovery and optimization of a novel series of PI3K-δ selective inhibitors. We first identified hits containing an isoindolinone scaffold using a combined ligand- and receptor-based virtual screening workflow, and then improved potency and selectivity guided by structural data and modeling. Careful optimization of molecular properties led to compounds with improved permeability and pharmacokinetic profile, and high potency in a whole blood assay.

Keywords: Isoindolinone; Lead Identification; PI3K-δ; Virtual screening.

MeSH terms

Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
Class I Phosphatidylinositol 3-Kinases / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Drug Evaluation, Preclinical
Humans
Molecular Structure
Phosphoinositide-3 Kinase Inhibitors / chemical synthesis
Phosphoinositide-3 Kinase Inhibitors / chemistry
Phosphoinositide-3 Kinase Inhibitors / pharmacology*
Phthalimides / chemical synthesis
Phthalimides / chemistry
Phthalimides / pharmacology*
Structure-Activity Relationship

Substances

Phosphoinositide-3 Kinase Inhibitors
Phthalimides
phthalimidine
Class I Phosphatidylinositol 3-Kinases
PIK3CD protein, human