2. Academic Validation
  3. 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

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.
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 Hu 1,  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

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.

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