Design, Synthesis, and Biological Evaluation of Quinazolin-4-one-Based Hydroxamic Acids as Dual PI3K/HDAC Inhibitors

A series of quinazolin-4-one
based hydroxamic acids was rationally
designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating
an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized
linker. Several of these dual inhibitors were highly potent (IC50 < 10 nM) and selective against PI3Kγ, δ and
HDAC6 enzymes and exhibited good antiproliferative activity against
multiple cancer cell lines. The lead compound 48c, induced
necrosis in several mutant and FLT3-resistant AML cell lines and primary
blasts from AML patients, while showing no cytotoxicity against normal
PBMCs, NIH3T3, and HEK293 cells. Target engagement of PI3Kδ
and HDAC6 by 48c was demonstrated in MV411 cells using
the cellular thermal shift assay (CETSA). Compound 48c showed good pharmacokinetics properties in mice via intraperitoneal
(ip) administration and provides a means to examine the biological
effects of inhibiting these two important enzymes with a single molecule,
either in vitro or in vivo.