Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors

Bioorg Med Chem Lett. 2023 Jul 15;91:129352. doi: 10.1016/j.bmcl.2023.129352.

Neil P Grimster ¹, Lakshmaiah Gingipalli ², Amber Balazs ², Bernard Barlaam ³, Scott Boiko ², Scott Boyd ³, Hannah Dry ², Frederick W Goldberg ³, Tim Ikeda ⁴, Tony Johnson ³, Sameer Kawatkar ², Paul Kemmitt ³, Scott Lamont ³, Olivier Lorthioir ³, Adelphe Mfuh ², Joe Patel ⁴, Andy Pike ³, Jon Read ⁵, Romulo Romero ², Ujjal Sarkar ², Li Sha ², Iain Simpson ³, Kun Song ², Qibin Su ², Haixia Wang ², David Watson ³, Allan Wu ⁴, Troy E Zehnder ², XiaoLan Zheng ², Shaolu Li ², Zhiqiang Dong ⁶, Dejian Yang ⁶, Yanwei Song ⁶, Peng Wang ⁶, Xuemei Liu ⁶, James E Dowling ², Scott D Edmondson ²

Affiliations

1 Oncology R & D, AstraZeneca, Waltham, USA. Electronic address: [email protected].
2 Oncology R & D, AstraZeneca, Waltham, USA.
3 Oncology R & D, AstraZeneca, Cambridge, UK.
4 Discovery Sciences R & D, AstraZeneca, Waltham, USA.
5 Discovery Sciences R & D, AstraZeneca, Cambridge, UK.
6 Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, PR China.

PMID: 37270074 DOI: 10.1016/j.bmcl.2023.129352

Abstract

Spleen tyrosine kinase (Syk) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of Syk has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of Syk, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.

Keywords

DLBCL; Kinase; Macrocycle; SYK.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-149895

Syk-IN-7

Syk Inhibitor

Syk

Cancer

Name
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