| Literature DB >> 32212730 |
Ashish Thakur1, Gregory J Tawa1, Mark J Henderson1, Carina Danchik1, Suiyang Liu2, Pranav Shah1, Amy Q Wang1, Garrett Dunn1, Md Kabir1, Elias C Padilha1, Xin Xu1, Anton Simeonov1, Surender Kharbanda2, Richard Stone2, Gurmit Grewal1.
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 (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.Entities:
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Year: 2020 PMID： 32212730 PMCID： PMC7238858 DOI： 10.1021/acs.jmedchem.0c00193
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446