2. Academic Validation
  3. SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3Kδ) inhibitors

SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3Kδ) inhibitors

  • Eur J Med Chem. 2017 Jan 5:125:1156-1171. doi: 10.1016/j.ejmech.2016.11.014.
Manman Wei 1,  Xi Zhang 2,  Xiang Wang 2,  Zilan Song 3,  Jian Ding 2,  Ling-Hua Meng 4,  Ao Zhang 5
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: lhmeng@simm.ac.cn.
  • 5 CAS Key Laboratory of Receptor Research, Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: aozhang@simm.ac.cn.
PMID: 27846451 DOI: 10.1016/j.ejmech.2016.11.014
Abstract

PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7.60 nM), respectively. It was 154-fold selective over PI3Kα, 133-fold selective against PI3Kβ, and 24-fold selective against PI3Kγ. Treatment of MOLT-4 and SU-DHL-6 cells with compound 8d for 1 h resulted in reduction of phosphorylation of both Akt (S473) and its downstream S6k1 (T389) in a concentration-dependent manner. Compound 8d showed potent anti-proliferative activity as well against T lymphoblast MOLT-4, suggesting its potential activity in T-cell leukemia.

Keywords

5-Alkynyl; Chronic lymphocytic leukemia; PI3Kδ; Quinazolinone; Structure-activity relationship.

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