Discovery of Novel Phosphoinositide-3-Kinase α Inhibitors with High Selectivity, Excellent Bioavailability, and Long-Acting Efficacy for Gastric Cancer

Phosphoinositide-3-kinase (PI3K) overexpressed in many
tumors is
a promising target for cancer therapy. However, due to toxicity from
the ubiquitous expression of PI3K in many tissues, the development
of PI3K inhibitors with high selectivity and low toxicity has become
an urgent need for tumor treatment. Herein, based on the HipHop, we designed and synthesized a series of 6-(4,6-dimorpholino-1,3,5-triazin-2-yl)­benzo­[d]­oxazol-2-amine derivatives as potent, selective, and long-acting
PI3Kα inhibitors. Compound 27 was determined with
potent PI3Kα inhibitory activity (IC50 = 4.4 nM),
which exhibited excellent selectivity for homologous PI3K enzymes
and a 370 kinome panel. Meanwhile, 27 featured favorable
stability (T1/2 > 10 h) and high bioavailability
(130%). Importantly, compound 27 exerted great antigastric
cancer activity in vivo when combined with taxol.
Collectively, these characteristics suggested 27 to be
a promising PI3K agent for cancer treatment.

磷脂酰肌醇3-激酶（PI3K）在多种肿瘤中过表达，是癌症治疗的极具潜力的靶点。然而，由于PI3K在诸多组织中广泛表达所带来的毒性，开发高选择性、低毒性的PI3K抑制剂已成为肿瘤治疗的迫切需求。本研究基于HipHop，设计并合成了一系列6-(4,6-二吗啉代-1,3,5-三嗪-2-基)苯并[d]恶唑-2-胺类衍生物，作为强效、高选择性且长效的PI3Kα抑制剂。化合物27展现出强效的PI3Kα抑制活性（IC50=4.4 nM），对同源PI3K酶家族及370激酶组谱均表现出优异的选择性。与此同时，化合物27具备良好的稳定性（半衰期T1/2>10 h）及较高的生物利用度（130%）。尤为重要的是，当与紫杉醇联用时，化合物27在体内展现出优异的抗胃癌活性。综上，上述特性表明化合物27是一款极具潜力的PI3K靶向抗癌治疗药物。