2. Academic Validation
  3. Discovery and Optimization of 4-Methylquinazoline Derivatives as Highly Selective PI3Kδ Inhibitors for the Treatment of Acute Lung Injury

Discovery and Optimization of 4-Methylquinazoline Derivatives as Highly Selective PI3Kδ Inhibitors for the Treatment of Acute Lung Injury

  • J Med Chem. 2026 Jun 11;69(11):13294-13319. doi: 10.1021/acs.jmedchem.6c00288.
Deyu Wu 1 2,  Mengyao Hao 1 2,  Shuhan Dong 1 2,  Wen Zhou 1 2,  Tianning Xiong 1 2,  Chengxia Mao 3,  Baolian Wang 3,  Mingchao Wang 1 2,  Songwen Lin 1 2,  Jing Jin 1 2,  Heng Xu 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 2 Beijing Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery and Translational Development, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 3 Department of Drug Metabolism, Beijing Key Laboratory of Key Technologies for Preclinical Research and Development of Innovative Drugs in Pharmacokinetics and Pharmacodynamics, State Key Laboratory of Digestive Health, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 100050 Beijing, P. R. China.
PMID: 42177646 DOI: 10.1021/acs.jmedchem.6c00288
Abstract

Phosphoinositide 3-kinase δ (PI3Kδ) has emerged as a promising therapeutic target for inflammatory respiratory diseases. Herein, we report the design and synthesis of a novel series of 4-methylquinazoline derivatives as potent and highly selective PI3Kδ inhibitors for the treatment of acute lung injury (ALI). Guided by structure-based drug design optimization of a pan-PI3K inhibitor scaffold, the lead compound 48 was identified, exhibiting single-digit nanomolar potency against PI3Kδ and exceptional selectivity over Other class I PI3K isoforms. Mechanistically, compound 48 effectively modulated immune responses by suppressing pro-inflammatory M1 macrophage polarization while promoting the anti-inflammatory M2 phenotype. Possessing favorable pharmacokinetic properties, compound 48 was evaluated in murine models of LPS-induced ALI and septic lung injury, where it significantly attenuated pulmonary edema and inflammatory infiltration. Collectively, compound 48 represents a promising preclinical candidate for the therapeutic intervention of ALI.

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