Synthesis and anti-tumor activity of pyrazole pyrimidine PI3K<italic>γ</italic>/<italic>δ</italic> inhibitors

Mao-qing Deng; Feng-ming Zou; Zi-ping QI; Chun Wang; Kai-li Long; Qing-wang Liu; Ao-li Wang; Jing Liu; Xiao-fei Liang

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Synthesis and anti-tumor activity of pyrazole pyrimidine PI3Kγ/δ inhibitors

VernacularTitle:吡唑并嘧啶类PI3Kγ/δ抑制剂的合成及抗肿瘤活性研究
Author: Mao-qing DENG ^{1
,

2} ; Feng-ming ZOU ^{1
,

3} ; Zi-ping QI ^{1
,

3} ; Chun WANG ^{1
,

2} ; Kai-li LONG ^{1
,

2} ; Qing-wang LIU ^{1
,

3} ; Ao-li WANG ^{1
,

3} ; Jing LIU ^{1
,

2
,

3} ; Xiao-fei LIANG ^{1
,

2
,

3}
Author Information

1. Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
2. University of Science and Technology of China, Hefei 230026, China
3. Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, China
Publication Type:Research Article
Keywords: PI3Kγ; PI3Kδ; tumor microenvironment; pyrazolo pyrimidine; anti-tumor
From: Acta Pharmaceutica Sinica 2024;59(7):2041-2052
CountryChina
Language:Chinese
Abstract: PI3Kγ and PI3Kδ have important regulatory roles in the immune system, and targeting these two subtypes helps to reshape the tumor microenvironment. PI3Kγ and PI3Kδ are potential targets for tumor immunotherapy. In this study, a series of new pyrazolopyrimidine derivatives were designed and synthesized on the basis of our previously reported PI3K inhibitors, resulting in the discovery of compound 16l as a potent and selective PI3Kγ/δ dual inhibitor. Compound 16l demonstrated strong biochemical potencies against PI3Kγ and PI3Kδ with IC₅₀ values of 0.11 and 0.79 nmol·L^-1. In cell-based assays, it potently inhibited the PI3Kγ and PI3Kδ mediated Akt S473 phosphorylation with EC₅₀ values of 3 and 7 nmol·L^-1. In vivo, compound 16l exhibited acceptable pharmacokinetic properties in Sprague-Dawley (SD) rats and suppressed the tumor growth in a MC38 syngeneic mouse model. The animal experiments were approved by the Animal Ethics Committee of Hefei Institutes of Physical Science, Chinese Academy of Sciences (approval number: DWLL-2000-06). In addition, no appreciable human ether-a-go-go-related gene (hERG) inhibition was observed for compound 16l even at 30 μmol·L^-1. These results suggested that compound 16l might be a potential research tool for studying the PI3Kγ/δ mediated signaling pathways.