Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Michelle S. Miller, Philip E. Thompson, Sandra B Gabelli

Research output: Contribution to journalReview article

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3K, PI3K, PI3K and PI3K have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues.

Original languageEnglish (US)
JournalBiomolecules
Volume9
Issue number3
DOIs
StatePublished - Feb 26 2019

Fingerprint

Phosphatidylinositol 3-Kinases
Protein Isoforms
Class I Phosphatidylinositol 3-Kinases
Pharmaceutical Chemistry
Immune System Diseases
Structure-Activity Relationship
Protein Binding
Carrier Proteins
Thrombosis
Binding Sites
Water
Neoplasms
Proteins

Keywords

  • isoform selectivity
  • p110
  • p85
  • phosphatidylinositol 3-kinase
  • PI3K
  • PIK3CA

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Structural Determinants of Isoform Selectivity in PI3K Inhibitors. / Miller, Michelle S.; Thompson, Philip E.; Gabelli, Sandra B.

In: Biomolecules, Vol. 9, No. 3, 26.02.2019.

Research output: Contribution to journalReview article

Miller, Michelle S. ; Thompson, Philip E. ; Gabelli, Sandra B. / Structural Determinants of Isoform Selectivity in PI3K Inhibitors. In: Biomolecules. 2019 ; Vol. 9, No. 3.
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