Phosphatidylinositol-3-Kinase (PI3K) and Histone Deacetylase (HDAC) Multitarget Inhibitors: An Update on Clinical and Preclinical Candidates
Alef D. S. Lima, Lídia M. Lima
TL;DR
This paper reviews multitarget inhibitors that block both PI3K and HDAC enzymes, which could lead to better cancer treatments.
Contribution
The paper provides a critical overview of recent dual PI3K/HDAC inhibitors and outlines design principles for future drug development.
Findings
Dual inhibition of PI3K and HDAC shows synergistic antitumor effects in cancer cells.
Fimepinostat is the first clinically tested multitarget inhibitor with balanced activity against both targets.
Structural diversity and activity profiles of multitarget inhibitors are analyzed to guide future drug design.
Abstract
Phosphatidylinositol-3-kinases (PI3Ks) constitute an important validated therapeutic class involved in crucial cellular processes, and their dysregulation is associated with cancer initiation and progression. Nonetheless, intrinsic and acquired resistance mechanisms associated with PI3K pathway modulation have underscored the need for alternative therapeutic strategies. In this context, recent studies have shown that simultaneous inhibition of PI3K and histone deacetylases (HDAC) promotes synergistic antitumor effects in different cancer cell lines. HDACs are validated epigenetic targets that are extensively explored in clinical practice and have a pharmacophore with versatility for structural modifications, which facilitates the design of multitarget inhibitors. This review examines the rational design and synthetic evolution of dual PI3K/HDAC inhibitors, an area catalyzed by the…
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Taxonomy
TopicsHistone Deacetylase Inhibitors Research · Protein Degradation and Inhibitors · PI3K/AKT/mTOR signaling in cancer