Discovery of Novel Indazoles as Potent and Selective PI3Kδ Inhibitors with High Efficacy for Treatment of Hepatocellular Carcinoma.

Jifeng Qi, Weihua Wang, Yongmei Tang, Shengying Lou, Jiaer Wang, Tao Yuan, Qiaojun He, Bo Yang, Hong Zhu, Sunliang Cui

Journal of medicinal chemistry 2022 Mar 10

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PI3Kδ inhibitors have been developed for treatment of B-cell malignancies and inflammatory and autoimmune diseases. However, their therapeutic role in solid tumors like hepatocellular carcinoma (HCC) is rarely reported. Thus, the development of potent and selective PI3Kδ inhibitors with a new chemotype and therapy is highly desirable. Through the scaffold-hopping strategy, indazole was first described as the core structure of propeller-shaped PI3Kδ inhibitors. A total of 26 indazole derivatives were designed and prepared to identify a novel compound 9x with good isoform selectivity, PK profile, and potency. Compared to Idelalisib and Sorafenib, the pharmacodynamic (PD) studies showed that 9x exhibits superior efficacy in HCC cell lines and xenograft models, and the mechanistic study showed that 9x robustly suppresses the downstream AKT pathway to induce subsequent apoptotic cell death in HCC models. Therefore, this work provides a new structural design of PI3Kδ inhibitors for a novel and efficient therapeutic small molecule toward HCC.

Citation

Jifeng Qi, Weihua Wang, Yongmei Tang, Shengying Lou, Jiaer Wang, Tao Yuan, Qiaojun He, Bo Yang, Hong Zhu, Sunliang Cui. Discovery of Novel Indazoles as Potent and Selective PI3Kδ Inhibitors with High Efficacy for Treatment of Hepatocellular Carcinoma. Journal of medicinal chemistry. 2022 Mar 10;65(5):3849-3865