Discovery of (S)-2-(1-(4-Amino-3-(3-fluoro-4-methoxyphenyl)-1 H-pyrazolo[3,4- d]pyrimidin-1-yl)propyl)-3-cyclopropyl-5-fluoroquinazolin-4(3 H)-one (IHMT-PI3Kδ-372) as a Potent and Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease

Feng Li; Xiaofei Liang; Zongru Jiang; Aoli Wang; Junjie Wang; Cheng Chen; Wenliang Wang; Fengming Zou; Ziping Qi; Qingwang Liu; Zhenquan Hu; Jiangyan Cao; Hong Wu; Beilei Wang; Li Wang; Jing Liu; Qingsong Liu

doi:10.1021/acs.jmedchem.0c01544

Discovery of (S)-2-(1-(4-Amino-3-(3-fluoro-4-methoxyphenyl)-1 H-pyrazolo[3,4- d]pyrimidin-1-yl)propyl)-3-cyclopropyl-5-fluoroquinazolin-4(3 H)-one (IHMT-PI3Kδ-372) as a Potent and Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease

J Med Chem. 2020 Nov 25;63(22):13973-13993. doi: 10.1021/acs.jmedchem.0c01544. Epub 2020 Nov 12.

Authors

Feng Li^{1

2}, Xiaofei Liang^{1

3}, Zongru Jiang^{1

3}, Aoli Wang^{1

3}, Junjie Wang^{1

2}, Cheng Chen^{1

2}, Wenliang Wang^{1

2}, Fengming Zou^{1

3}, Ziping Qi^{1

3}, Qingwang Liu^{1

3}, Zhenquan Hu¹, Jiangyan Cao^{1

2}, Hong Wu^{1

3}, Beilei Wang^{1

3}, Li Wang^{1

3}, Jing Liu^{1

3

4}, Qingsong Liu^{1

2

3

4

5}

Affiliations

¹ Anhui Province Key Laboratory of Medical Physics and Technology; CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
² University of Science and Technology of China, Hefei, Anhui 230026, P. R. China.
³ Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
⁴ Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China.
⁵ Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui 230601, P. R. China.

PMID: 33180507
DOI: 10.1021/acs.jmedchem.0c01544

Abstract

Accumulated pieces of evidence have shown that PI3Kδ plays a critical role in chronic obstructive pulmonary disease (COPD). Using a fragment-hybrid approach, we discovered a potent and selective PI3Kδ inhibitor (S)-18. In the biochemical assay, (S)-18 inhibits PI3Kδ (IC₅₀ = 14 nM) with high selectivity over other class I PI3Ks (56∼83 fold). (S)-18 also achieves good selectivity over other protein kinases in the kinome (S-score (35) = 0.015). In the cell, (S)-18 selectively and potently inhibits the PI3Kδ-mediated phosphorylation of AKT T308 but not other class I PI3K-mediated signaling. Additionally, (S)-18 exhibits no apparent inhibitory effect on CYP isoforms except for a moderate effect on CYP2C9. Furthermore, it shows no apparent inhibitory activity against hERG (IC₅₀ > 10 μM). In vivo, (S)-18 displays favorable PK properties for inhaled delivery and improves lung function in a rodent model of pulmonary inflammation. These results suggest that (S)-18 might be a new potential therapeutic candidate for COPD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation / drug effects*
Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
Drug Discovery*
Male
Molecular Docking Simulation
Phosphoinositide-3 Kinase Inhibitors / chemistry*
Phosphoinositide-3 Kinase Inhibitors / pharmacology*
Pulmonary Disease, Chronic Obstructive / drug therapy*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

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