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Exploring the PI3Kα and γ binding sites by homology modeling and inhibitors utilizing a 2,6-disubstituted isonicotinic scaffold

Cherian, Philip T.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1243016151

Abstract Details

2009, PhD, University of Cincinnati, Pharmacy : Pharmaceutical Sciences.
Phosphatidylinositol 3-OH kinases (PI3Ks) are dual specific lipid and protein kinases that catalyze the synthesis of the lipid second messenger Phosphatidylinositol-3,4,5-trisphosphate (PIP3) and influence multiple cellular processes including cell growth, proliferation, survival and motility. PI3Ks are divided into three classes I, II and III and the class I contains four isoforms, namely p110α, β, δ and γ. Of these, the p110α isoform (PI3Kα) is an important therapeutic target in cancer as the PIK3CA gene that encodes the p110α catalytic subunit is frequently mutated in a variety of cancers. Though several classes of compounds that inhibit the class I enzymes have been reported, development of inhibitors selective for the PI3Kα still remains a major challenge. In accordance with the ongoing research efforts towards the development of isoform selective inhibitors, we explored the differences between the p110α and γ binding sites using a structure-based approach. The study entailed the building of a p110α homology model, development of a novel scaffold that provided the ease of assembly and diversification and designing of focused chemical libraries based on our modeling studies.Advancement in protein structure prediction methods has simplified the process of obtaining reliable 3D structures of target proteins. Using the p110α protein sequence and X-ray structure of p110γ, a homology model of p110α was constructed and refined. This model proved to be in good agreement with the later published X-ray structure of p110α (2rd0). Using this model and literature analysis of PI3K inhibitors, we designed the 2,6-disubstituted isonicotinic scaffold for our study. This scaffold was evaluated for its synthetic feasibility and biological activity by designing, synthesizing and testing an initial set of derivatives. These compounds inhibited the activity of the recombinant purified PI3Kα and γ in our in vitro lipid kinase assay and showed inhibition of PI3K-dependent survival of cell lines derived from the hematopoietic FL5.12 cells. The most potent compound in the series (compound 28) showed potency in the low micromolar range with 7-fold selectivity for PI3Kα. The chemistry developed during the synthesis of the above series provided straightforward access to three chemical libraries. Accordingly, the three regions of the scaffold were modified in order to explore the hydrogen bonding, bulk and polarity as predicted by our model. These modifications led to the development of compound 63 which showed >10-fold selectivity for PI3Kα vs. PI3Kγ and was more potent in the cell assay than previous compounds. Based on our docking studies, the selectivity of this compound can be attributed to its interaction with Arg770 and Trp780 of p110α. Overall we demonstrate the utility of homology modeling and the 2,6-disubstituted scaffold for exploring the p110α and γ binding sites and anticipate that the data generated during this study may be useful toward the development of more potent and selective PI3Kα and γ inhibitors.
James Knittel, PhD (Committee Chair)
Giovanni Pauletti, PhD (Committee Member)
Frank Ebetino, PhD (Committee Member)
Matthew Wortman, PhD (Committee Member)
David Plas, PhD (Committee Member)
170 p.
Biomedical Research; Chemistry; Pharmaceuticals
kinase inhibitors; homology modeling; SAR

Recommended Citations

Citations

  • Cherian, P. T. (2009). Exploring the PI3Kα and γ binding sites by homology modeling and inhibitors utilizing a 2,6-disubstituted isonicotinic scaffold [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1243016151

    APA Style (7th edition)

  • Cherian, Philip. Exploring the PI3Kα and γ binding sites by homology modeling and inhibitors utilizing a 2,6-disubstituted isonicotinic scaffold. 2009. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1243016151.

    MLA Style (8th edition)

  • Cherian, Philip. "Exploring the PI3Kα and γ binding sites by homology modeling and inhibitors utilizing a 2,6-disubstituted isonicotinic scaffold." Doctoral dissertation, University of Cincinnati, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1243016151

    Chicago Manual of Style (17th edition)

ucin1243016151
859
© 2009, some rights reserved.Creative Commons License Exploring the PI3Kα and γ binding sites by homology modeling and inhibitors utilizing a 2,6-disubstituted isonicotinic scaffold by Philip T. Cherian is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.