Discovery of Pyrazolo[1,5-a]pyridine Derivatives as Potent and Selective PI3Kγ/δ Inhibitors,Journal of Medicinal Chemistry

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Discovery of Pyrazolo[1,5-a]pyridine Derivatives as Potent and Selective PI3Kγ/δ Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-20 , DOI: 10.1021/acs.jmedchem.4c00817
Chun Wang _{1,

2} , Fengming Zou _{1,

3,

4} , Ziping Qi _{1,

3,

4} , Qingwang Liu _{1,

3,

4} , Lijuan Shen _{1,

2} , Xinyu Yuan _{1,

2} , Maoqing Deng _{1,

2} , Aoli Wang _{1,

3,

4} , Beilei Wang _{1,

3,

4} , Li Wang _{1,

3,

4,

5} , Xiaofei Liang _{1,

2,

3,

4} , Qingsong Liu _{1,

2,

3,

4,

5} , Jing Liu _{1,

2,

3,

4,

5}

Affiliation

PI3Kγ and PI3Kδ plays critical roles in exerting immunosuppression by targeting regulatory T cells and myeloid cells. Dual inhibition of PI3Kγ and PI3Kδ has emerged as a novel therapeutic strategy for cancer immunotherapy. We herein report a series of pyrazolopyridine derivatives with distinct scaffolds as potent and selective dual inhibitors of PI3Kγ and PI3Kδ. Among them, 20e (IHMT-PI3K-315) displays an IC₅₀ value of 4.0 and 9.1 nM against PI3Kγ and PI3Kδ respectively in biochemical assays. Meanwhile, it potently inhibits PI3Kγ and PI3Kδ-mediated phosphorylation of AKT S473 with EC₅₀ values of 0.028 and 0.013 μM in cellular assays. In addition, 20e exhibits a favorable selectivity profile in protein kinases at 1 μM. In bone marrow-derived macrophages (BMDM), 20e can repolarize the M2 phenotype to the M1 phenotype. In vivo, 20e demonstrates acceptable pharmacokinetic properties and suppresses tumor growth in a MC38 syngeneic mouse model.

中文翻译：

发现吡唑并[1,5-a]吡啶衍生物作为有效和选择性 PI3Kγ/δ 抑制剂

PI3Kγ 和 PI3Kδ 通过靶向调节性 T 细胞和骨髓细胞发挥免疫抑制作用。 PI3Kγ 和 PI3Kδ 的双重抑制已成为癌症免疫治疗的一种新型治疗策略。我们在此报告了一系列具有独特支架的吡唑并吡啶衍生物，作为 PI3Kγ 和 PI3Kδ 的有效和选择性双重抑制剂。其中， 20e ( IHMT-PI3K-315 ) 在生化检测中对 PI3Kγ 和 PI3Kδ 的 IC ₅₀值分别为 4.0 和 9.1 nM。同时，它可有效抑制 PI3Kγ 和 PI3Kδ 介导的 AKT S473 磷酸化，在细胞测定中 EC ₅₀值为 0.028 和 0.013 μM。此外， 20e在 1 μM 的蛋白激酶中表现出良好的选择性。在骨髓源性巨噬细胞 (BMDM) 中， 20e可以将 M2 表型重新极化为 M1 表型。在体内， 20e在 MC38 同基因小鼠模型中表现出可接受的药代动力学特性并抑制肿瘤生长。

更新日期：2024-08-20

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