2. Academic Validation
  3. Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design

Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design

  • ACS Med Chem Lett. 2013 Dec 10;5(2):138-42. doi: 10.1021/ml400378e.
Yanlong Zhao 1,  Xi Zhang 2,  Yingyi Chen 1,  Shaoyong Lu 1,  Yuefeng Peng 3,  Xiang Wang 2,  Chengliang Guo 2,  Aiwu Zhou 1,  Jingmiao Zhang 1,  Yu Luo 1,  QianCheng Shen 1,  Jian Ding 2,  Linghua Meng 2,  Jian Zhang 1
Affiliations

Affiliations

  • 1 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University, School of Medicine , Shanghai 200025, China.
  • 2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
  • 3 Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS) , Guangdong, Shenzhen 518055, China.
PMID: 24900786 DOI: 10.1021/ml400378e
Abstract

The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for Cancer therapy. We determined the crystal structure of the human PI3Kα-PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3Kα-9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3Kα inhibitors.

Keywords

PI103; PI3K; cancer therapy; crystal structure; drug design.

Figures