Wei Manman, Zhang Xi, Wang Xiang, Song Zilan, Ding Jian, Meng Ling-Hua, Zhang Ao
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.
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China.
Eur J Med Chem. 2017 Jan 5;125:1156-1171. doi: 10.1016/j.ejmech.2016.11.014. Epub 2016 Nov 9.
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.
PI3Kδ是B细胞恶性肿瘤异常信号转导中的关键成分，因此特异性靶向PI3Kδ已成为慢性淋巴细胞白血病（CLL）一种有吸引力的分子靶向治疗方法。在此，我们描述了基于首个获得美国食品药品监督管理局（FDA）批准的抑制剂idelalisib的一系列5-炔基取代的PI3Kδ抑制剂的发现和优化过程。确定带有1-吗啉代己-5-炔-1-酮部分作为C5取代基的化合物8d对PI3Kδ（3.82 nM）和SU-DHL-6细胞（7.60 nM）分别具有高效力。它对PI3Kα的选择性为154倍，对PI3Kβ的选择性为133倍，对PI3Kγ的选择性为24倍。用化合物8d处理MOLT-4和SU-DHL-6细胞1小时，导致Akt（S473）及其下游S6k1（T389）的磷酸化以浓度依赖性方式降低。化合物8d对T淋巴母细胞MOLT-4也显示出有效的抗增殖活性，表明其在T细胞白血病中的潜在活性。
