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

Abstract

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 R 1 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: PI3K, PI103, crystal structure, drug design, cancer therapy T he lipid kinase family of phosphatidylinositol 3-kinases (PI3Ks) plays pivotal roles in many cellular processes, including proliferation, survival, differentiation, and metabolism. 1−3 Class I PI3K, the best physiologically, biochemically, and structurally characterized member of the PI3K family, consists of four isoforms, α, β, γ, and δ. Each isoform is a heterodimer that comprises a p110 catalytic subunit and a p85 regulatory subunit. Upon insulin and growth factor stimulation, PI3Ks phosphorylate phosphatidylinositol-3,4-bisphosphate (PIP2) to produce phosphatidylinositol-3,4,5-triphosphate (PIP3). The cellular level of PIP3 is also tightly regulated by phosphatases, such as the phosphatase and tensin homologue (PTEN), which dephosphorylates PIP3 back to PIP2. 4,5 The PI3K pathway is frequently deregulated in a wide range of tumor types as a result of hyperactivation of upstream growth factor signaling, mutation, or loss of PTEN, 6 and oncogenic mutations in PIK3CA, 7 which provides further evidence of the role of PI3K in tumorigenesis. Moreover, accumulating evidence indicates that hyperactivation of PI3Kα is inextricably linked to cancer survival and resistance to existing therapies in a great proportion of human cancers. 8 Therefore, targeting PI3Ks with small-molecular-weight inhibitors provides an attractive opportunity for cancer therapy and for overcoming resistance to current therapies, and thus, significant efforts have recently been made to develop PI3K inhibitors. 9 With multiple ongoing efforts in academic and industrial organizations to develop clinically relevant inhibitors against PI3K, a number of inhibitors have already entered clinical trials. 2,10 PI103 is one of the first synthesized PI3K inhibitors; it belongs to the pyridinylfuranopyrimidine class and inhibits PI3K in an ATP-competitive manner with selectivity toward PI3Kα. 11 PI103 has already demonstrated significant antitumor activity against several human tumor xenografts, especially those with well-established abnormalities in the P...

Molecular modeling based approach, synthesis, and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kα)

“…11,13 Due to the oncogenic potential of PI3Ka and its negative regulator PTEN, PI3Ka has emerged as an attractive target for anticancer drug design. 14,15 Several chemical scaffolds have been designed and synthesized targeting PI3Ka [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] and some of these have been investigated in clinical trials. [31][32][33][34] We previously reported the pharmacophore features for PI3Ka inhibitors and identified potential inhibitors.…”

Design, synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as mTOR/PI3Kα inhibitors

“…And three compounds also displayed moderate to excellent PI3Ka kinase inhibition activity with IC 50 values from 1.805 mM to 2.352 mM. The most promising compound 16i showed good inhibitory activity against mTOR/PI3Ka kinase and good antitumor potency for H460 and PC-3 cell lines with IC 50 values of 0.16 ± 0.03 mM, 2.35 ± 0.19 mM, 1.20 ± 0.23 mM and 0.85 ± 0.04 mM, which were 8.6, >5, 7.9 and 19.1 times more active than compound I (1.37 ± 0.07 mM, >10 mM, 9.52 ± 0.29 mM, 16.27 ± 0.54 mM), respectively. The initial SARs and docking studies showed that the chromone moieties were necessary for the activity of these compounds.…”

“…Three compounds (10i,16hei) are more active than compound I against PI3Ka kinase. The most promising compound 16i showed good inhibitory activity against mTOR, PI3Ka kinase and good cytotoxicity for H460 and PC-3 cell lines with IC 50 values of 0.16 ± 0.03 mM, 2.35 ± 0.19 mM, 1.20 ± 0.23 mM and 0.85 ± 0.04 mM, which were 8.6, 7.9 and 19.1 times more active than compound I (1.37 ± 0.07 mM, 9.52 ± 0.29 mM, 16.27 ± 0.54 mM), respectively.…”

“…Based on the in vitro inhibition results, we selected compound 16i, our best mTOR/PI3Ka inhibitor in this study, as ligand example, and the structures of mTOR (PDB ID code:4JT6 [15]) and PI3Ka (PDB ID code:4L23 [16]) were selected as the docking models.…”

“…For docking purposes, the three-dimensional structures of the mTOR (PDB code: 4JT6) and PI3Ka (PDB code: 4L23) were obtained from RCSB Protein Data Bank [15,16]. Hydrogen atoms were added to the structure allowing for appropriate ionization at physiological pH and waters were removed.…”