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Bioorg Med Chem Lett. 2019 Sep 15;29(18):2575-2580. doi: 10.1016/j.bmcl.2019.08.004. Epub 2019 Aug 5.

Design of selective PI3Kδ inhibitors using an iterative scaffold-hopping workflow.

Author information

1
Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA, USA. Electronic address: xavier.fradera@merck.com.
2
Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.
3
Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA, USA.
4
Proteros Biostructures GmbH, Martinsried, Germany.
5
In vitro Pharmacology, Merck & Co., Inc., Boston, MA, USA.

Abstract

PI3Kδ mediates key immune cell signaling pathways and is a target of interest for multiple indications in immunology and oncology. Here we report a structure-based scaffold-hopping strategy for the design of chemically diverse PI3Kδ inhibitors. Using this strategy, we identified several scaffolds that can be combined to generate new PI3Kδ inhibitors with high potency and isoform selectivity. In particular, an oxindole-based scaffold was found to impart exquisite selectivity when combined with several hinge binding motifs.

KEYWORDS:

Oxindole; PI3Kδ; Scaffold-hopping; Structure-based drug design

PMID:
31416665
DOI:
10.1016/j.bmcl.2019.08.004

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