Dong Jiaqiang, Huang Jingjie, Zhou Ji, Tan Ye, Jin Jing, Tan Xi, Wang Bei, Yu Tao, Wu Chengde, Chen Shuhui, Wang Tie-Lin
Luoxin Pharmaceutical (Shanghai) Co., Ltd., Building 1 and First-Third Floors, Building 2, No. 85 Faladi Road, China (Shanghai) Pilot Free Trade Zone, Shanghai 201203, China.
Domestic Discovery Service Unit, WuXi AppTec Co., Ltd., 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
ACS Med Chem Lett. 2020 Jun 10;11(7):1463-1469. doi: 10.1021/acsmedchemlett.0c00239. eCollection 2020 Jul 9.
Phosphoinositide 3-kinases (PI3Ks) mediate a series of events related to cell growth, proliferation, survival, and differentiation. Overexpression of PI3Ks can lead to the dysregulation of cell homeostasis and cause tumorigenesis. In this study, rationally designed compounds were investigated as PI3Kα-selective inhibitors. Our efforts culminated in the discovery of a series of quinazolin-4(3)-one derivatives with 2-substituted--methylpropanamide substitutions as PI3Kα-selective inhibitors. The best compound, , has PI3Kα enzymatic and cellular IC values of 1.8 and 12.1 nM, respectively. It exhibits biochemical selectivities for PI3Kα over PI3Kβ/δ/γ of 150/7.72/7.67-fold and cellular selectivities of 115/15.1/>826-fold, respectively. Compound is 59% orally bioavailable with a dose-normalized AUC of 3090 nM. These effects translated into in vivo conditions, as significantly time- and dose-dependently inhibited phosphorylation of Akt in BT-474 subcutaneous xenograft mice and inhibited tumor growth.
磷脂酰肌醇3-激酶（PI3Ks）介导一系列与细胞生长、增殖、存活和分化相关的事件。PI3Ks的过表达可导致细胞稳态失调并引发肿瘤发生。在本研究中，对合理设计的化合物作为PI3Kα选择性抑制剂进行了研究。我们的努力最终发现了一系列具有2-取代的甲基丙酰胺取代基的喹唑啉-4(3)-酮衍生物作为PI3Kα选择性抑制剂。最佳化合物的PI3Kα酶活性和细胞IC值分别为1.8和12.1 nM。它对PI3Kα相对于PI3Kβ/δ/γ的生化选择性分别为150/7.72/7.67倍，细胞选择性分别为115/15.1/>826倍。化合物的口服生物利用度为59%，剂量标准化AUC为3090 nM。这些作用在体内条件下也得到体现，因为该化合物在BT-474皮下异种移植小鼠中显著地时间和剂量依赖性地抑制Akt磷酸化并抑制肿瘤生长。
