MYC is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks MYC expression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dualactivity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.T he MYC gene is frequently altered in human cancer. It encodes a transcription factor that binds to and regulates nearly 10-15% of genes in the human genome (1-3). The MYC targets mediate fundamental biological processes necessary for cell survival and general well-being, ranging from gene-expression and cell-cycle programs to cell proliferation and response to DNA damage, thereby establishing MYC as a global transcriptional regulator. MYC is overexpressed or amplified in many human cancers, which results in genome instability and deregulation of an array of signaling pathways responsible for malignant transformation. MYC expression level as well as synthesis, stability, and posttranslational modifications (PTMs) of the MYC protein are tightly regulated via several pathways, including PI3K-AKTmTOR and RAS-MAPK (4). Particularly, PI3K activation blocks MYC degradation through inhibiting GSK3β-dependent MYC phosphorylation at threonine 58, elevating MYC levels and inducing MYC-dependent oncogenic programs (4, 5).MYC gene expression has recently been linked to the activity of the BET (bromodomains and extraterminal domain) family of transcriptional coactivators (6-9). The BET protein BRD4 is found enriched at MYC and other oncogenes superenhancer and promoter regions, and transcriptional silencing of MYC coincides with the release of BET proteins from its locus, indicating that BET proteins can regulate MYC expression (10, 11). BRD4 itself is linked to multiple human malignancies: It forms chromosomal translocations in squamous carcinoma and NUT midline carcinoma, plays a role in progression of acute myeloid leukemia, and is up-regulated in breast cancer (7,(12)(13)(14). BRD4 contains a pair of bromodomains (BDs) that belong to the family of evolutionarily conserved structural modules that recognize acetyllysine PTMs in histones and nonhistone proteins (15, 16). Interestingly, BD1 and BD2 of BRD4 have distinct acetyllysine binding functions (17). BD1 binds to diacetylated histones, including histone H4 diacetylated at lysine 5 and lysine 8 (H4K5acK8ac), and this interaction helps to recruit or stabilize BRD4-containing transcription complexes at target gene promoters and enhancers. The se...

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This article describes an efficient method for the solid phase synthesis of benzopiperazinones (1,2,3,4tetrahydroquinoxalin-2-ones) with four independently variable functional groups. Commercially available 4-fluoro-3-nitrobenzoic acid (FNBA) was anchored directly to Wang resin and to amino acid-containing Wang resin. Treatment of these resins with amino acid derivatives afforded enantiomerically pure aniline intermediates via an ipso-fluoro displacement in high yields. Reduction of the aromatic nitro group with aqueous 2 M SnCl 2 , followed by spontaneous intramolecular cyclization, afforded benzopiperazinones in good yields. Complete acylation of the aniline site (N4) was achieved using several chloro-or thiochloroformates and NaHCO 3 in anhyd THF/DMF at 80 °C under an argon atmosphere. Alkylation of the anilide nitrogen (N1) with lithiated (S)-(-)-4-benzyl-2-oxazolidinone and benzyl bromide afforded alkylated benzopiperazinones in good yields with a high enantiomeric excess (>95% ee). A number of side reactions including racemization were discovered in our studies and are addressed.