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

Abstract

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 (IC 50 < 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.

Recent Advances in Small Molecular Modulators Targeting Histone Deacetylase 6

“…The limited clinical efficacy of PI3K inhibitors promotes the development of combinational therapies or chimeric PI3K MTDs. Thakur et al developed a series of chimeras by incorporating HDAC ZBG into the solvent-exposed region of PI3K inhibitor idelalisib [113]. The linker part was systematically explored, and compound 49 with a phenylhydroxamate motif maintained a high potency against PI3Kγ and PI3Kδ with IC 50 values of 9.0 and 7.0 nM, respectively.…”

Multitarget Inhibition of Histone Deacetylase (HDAC) and Phosphatidylinositol‐3‐kinase (PI3K): Current and Future Prospects

“…To design HDAC and PI3K inhibitors with a better toxicity profile and a wider therapeutic window, Thakur and colleagues proposed the selective inhibition of specific isoforms of HDAC and PI3K [119] . The PI3K/HDAC dual inhibitors were designed by analyzing the crystal structures of idelalisib ( 5 ) in PI3Kδ [120] and vorinostat ( 1 ) in HDAC2 [92] .…”

“…The PI3Kα is widely expressed in the body and also is related with the insulin signaling pathway and is related with the hyperglycemia [29,30,32] . They observed that the carbonyl and fluoro group in the quinazolinone extended into the solvent exposed region and enabled the introduction of the HDAC pharmacophore (linker and zinc binding group) [119] (Figure 11). From the SAR studies, several compounds acted as potent and selective PI3Kδ/PI3Kγ/HDAC6 inhibitors with good cellular potencies against a panel of 60 different cancer cell lines.…”

“…From the SAR studies, several compounds acted as potent and selective PI3Kδ/PI3Kγ/HDAC6 inhibitors with good cellular potencies against a panel of 60 different cancer cell lines. Compound 22 was identified as a potent multitarget inhibitor (PI3Kδ IC 50 =7.0 nM, PI3Kγ IC 50 =9.0 nM and HDAC6 IC 50 =12 nM) (Table 2) with high kinome selectivity and potent anti‐proliferative activity against various cancer cell lines [119] . Given the promising profile of compound 22 , the in vitro pharmacokinetics (PK) was evaluated and showed that this compound presented low human liver microsome (HLM) stability and low cell permeability (Caco‐2 permeability assay).…”

“…After oral administration, it presented an oral bioavailability (%F) of only 0.7 %, and the intraperitoneal (ip) administration will serve as the preferred dosing route for the in vivo anti‐tumor efficacy study. Lead optimization efforts will be necessary to develop inhibitors with a favorable in vivo PK profile [119] …”