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

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

  • J Med Chem. 2022 Jul 28;65(14):9873-9892. doi: 10.1021/acs.jmedchem.2c00549.
Yi Hou 1 2,  Fang Zhang 1 2,  Wenjian Min 1 2,  Kai Yuan 1 2,  Wenbin Kuang 1 2,  Xiao Wang 1 2,  Yasheng Zhu 1 2,  Chengliang Sun 1 2,  Fei Xia 1 2,  Yanyin Wang 1 2,  Haolin Zhang 1 2,  Linping Wang 1 2,  Peng Yang 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
PMID: 35834807 DOI: 10.1021/acs.jmedchem.2c00549
Abstract

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.

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