Synthesis and Cancer Stem Cell-Based Activity of Substituted 5-Morpholino-7H-thieno[3,2-b]pyran-7-ones Designed as Next Generation PI3K Inhibitors

Morales, Guillermo A.; Garlich, Joseph R.; Su, Jingdong; Peng, Xiaodong; Newblom, Jessica; Weber, Kevin T.; Durden, Donald L.

doi:10.1021/jm301522m

Cited by 51 publications

(45 citation statements)

References 44 publications

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“…We have previously shown that 5-morpholino-7H-thieno[3,2-b]pyran-7-one (TP-scaffold) represents a promising class of PI3K inhibitors: Screening a panel of >200 kinases, we found that SF2523 is a highly selective and potent inhibitor of PI3K, particularly of the α isoform of PI3K (PI3Kα) (30). To assess SF2523 activity in the cellular context, we examined the effect of this compound on the PI3K signaling pathway in a neuroblastoma SKNBE2 cell line.…”

Section: Resultsmentioning

confidence: 99%

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Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

Andrews

Singh

Joshi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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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Section: Resultsmentioning

confidence: 99%

“…Normal rabbit IgG, protein A/G agarose beads, Cyclin D1, and MYC antibodies were from Santa Cruz Biotechnology, and anti-BRD4 antibody was obtained from Bethyl Laboratories. SF2523 and SF2535 were synthesized as described (30), and synthesis of SF2558HA will be reported elsewhere.…”

Section: Methodsmentioning

confidence: 99%

Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

Andrews

Singh

Joshi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

101

118

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“…PI-103, BKM120, and PF4691502 were purchased from Selleck chemicals. SF2523 and SF1126 were obtained from SignalRx Pharmaceuticals (29,30 0 -diamidino-2-phenylindole (DAPI), hyaluronidase type V, and DNase I were from Sigma.…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

“…2B). In addition to pan-PI3K inhibitors in clinical trial, we used SF2523, a novel pan-PI3K inhibitor developed in collaboration with SignalRx Pharmaceuticals (30), to see the effect of this PI3K inhibitor on HIFa stabilization. SF2523 blocked accumulation of HIF1a and HIF2a in dose-dependent manner (Fig.…”

Section: Inhibition Of Pi3k/akt Pathway Blocks the Hypoxic Induction mentioning

confidence: 99%

A Macrophage-Dominant PI3K Isoform Controls Hypoxia-Induced HIF1α and HIF2α Stability and Tumor Growth, Angiogenesis, and Metastasis

Joshi

Singh

Zulcic

et al. 2014

Molecular Cancer Research

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Tumor growth, progression, and response to the hypoxic tumor microenvironment involve the action of hypoxia-inducible transcription factors, HIF1 and HIF2. HIF is a heterodimeric transcription factor containing an inducible HIFa subunit and a constitutively expressed HIFb subunit. The signaling pathways operational in macrophages regulating hypoxia-induced HIFa stabilization remain the subject of intense investigation. Here, it was discovered that the PTEN/PI3K/AKT signaling axis controls hypoxia-induced HIF1a (HIF1A) and HIF2a (EPAS1) stability in macrophages. Using genetic mouse models and pan-PI3K as well as isoform-specific inhibitors, inhibition of the PI3K/AKT pathway blocked the accumulation of HIFa protein and its primary transcriptional target VEGF in response to hypoxia. Moreover, blocking the PI3K/AKT signaling axis promoted the hypoxic degradation of HIFa via the 26S proteasome. Mechanistically, a macrophage-dominant PI3K isoform (p110g) directed tumor growth, angiogenesis, metastasis, and the HIFa/VEGF axis. Moreover, a pan-PI3K inhibitor (SF1126) blocked tumor-induced angiogenesis and inhibited VEGF and other proangiogenic factors secreted by macrophages. These data define a novel molecular mechanism by which PTEN/PI3K/AKT regulates the proteasome-dependent stability of HIFa under hypoxic conditions, a signaling pathway in macrophages that controls tumor-induced angiogenesis and metastasis.

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“…9) Subsequent PI3K phosphorylate the 3′-hydroxyl group of phosphatidyl inositol 4,5-bisphosphate (PIP2) to generate phosphatidyl inositol 3,4,5-triphosphate (PIP3), which lead to activation of downstream signaling pathways. 10) The cellular levels of PIP3 are negatively regulated by phosphatase and tensin homolog deleted from chromosome 10 (PTEN), which is a phosphatase that converts PIP3 back to PIP2. 11,12) PI3K and PTEN are contradictory of oncogenic signaling.…”

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confidence: 99%

Discovery of Chromeno[4,3-c]pyrazol-4(2H)-one Containing Carbonyl or Oxime Derivatives as Potential, Selective Inhibitors PI3Kα

et al. 2016

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A series of novel chromeno[4,3-c]pyrazol-4(2H)-one containing carbonyl or oxime derivatives (4a-n, 5a-n) have been synthesized and evaluated their biological activities as phosphatidyl inositol 3-kinase (PI3K) inhibitors. Out of them, compound 5l showed the most potent antiproliferative activities against HCT-116 with IC 50 of 0.10 µM in vitro, and exhibited the most potent activity for PI3Kα with the value of 0.012 µM. Docking simulation of 5l into PI3Kα active site were performed to determine the probable binding model, and it indicated that compound 5l could be optimized as a potential inhibitor of PI3Kα in the further study. Key words chromeno[4,3-c]pyrazol-4(2H)-one derivative; inhibitor; antiproliferativeThree distinct classes of lipid phosphatidyl inositol 3-kinases (PI3Ks), as a family, play a key role in cellular processes by regulating functions such as cell metabolism, proliferation, differentiation, motility, and intracellular trafficking.

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Synthesis and Cancer Stem Cell-Based Activity of Substituted 5-Morpholino-7H-thieno[3,2-b]pyran-7-ones Designed as Next Generation PI3K Inhibitors

Cited by 51 publications

References 44 publications

Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

A Macrophage-Dominant PI3K Isoform Controls Hypoxia-Induced HIF1α and HIF2α Stability and Tumor Growth, Angiogenesis, and Metastasis

Discovery of Chromeno[4,3-<i>c</i>]pyrazol-4(2<i>H</i>)-one Containing Carbonyl or Oxime Derivatives as Potential, Selective Inhibitors PI3Kα

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