bims-drucaf Biomed News
on Drugs targeting chromatin associated factor in cancer therapy
Issue of 2020‒08‒16
thirteen papers selected by
Tian Tian
Vall d’Hebron Institute of Oncology
  1. The Ubiquitin-Proteasome Pathway and Epigenetic Modifications in Cancer.
  2. DNA Methylation as a Therapeutic Target for Bladder Cancer.
  3. The epigenomics of sarcoma.
  4. Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases.
  5. Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1).
  6. A triple action CDK4/6-PI3K-BET inhibitor with augmented cancer cell cytotoxicity.
  7. Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells.
  8. Flavonoids potentiated anticancer activity of cisplatin in non-small cell lung cancer cells in vitro by inhibiting histone deacetylases.
  9. Myeloid cell leukemin-1 inhibitors: a growing arsenal for cancer therapy.
  10. Functional characterization of a PROTAC directed against BRAF mutant V600E.
  11. Design, synthesis and biological evaluation of novel HDAC inhibitors with improved pharmacokinetic profile in breast cancer.
  12. BRD4 prevents the accumulation of R-loops and protects against transcription-replication collision events and DNA damage.
  13. Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas.
  1. Anticancer Agents Med Chem. 2020 Aug 10.
    The Ubiquitin-Proteasome Pathway and Epigenetic Modifications in Cancer.
    Azmi Yerlikaya, Ertan Kanbur, Bruce A Stanley, Emrah Tümer.
      BACKGROUND: The ubiquitin-proteasome pathway is involved in almost all cellular processes (cell cycle, gene transcription and translation, cell survival and apoptosis, cell metabolism and protein quality control) mainly through the specific degradation of majority of intracellular proteins (>80%) or partial processing of transcription factors (e.g., NF-κB). A growing amount of evidence now indicates that epigenetic changes are also regulated by the ubiquitin-proteasome pathway. Recent studies indicate that epigenetic regulations are equally crucial for almost all biological processes as well as for pathological conditions such as tumorigenesis, as compared to non-epigenetic control mechanisms (i.e., genetic alterations or classical signal transduction pathways).OBJECTIVE: Here we reviewed the recent work highlighting the interaction of the ubiquitin-proteasome pathway components (e.g., ubiquitin, E1, E2 and E3 enzymes and 26S proteasome) with epigenetic regulators (histone deacetylases, histone acetyltransferases and DNA methyltransferases).
    RESULTS: Alterations in the regulation of the ubiquitin-proteasome pathway have been discovered in many pathological conditions. For example, a 2- to 32-fold increase in proteasomal activity and/or subunits has been noted in primary breast cancer cells. Although proteasome inhibitors have been successfully applied in the treatment of hematological malignancies (e.g., multiple myeloma), the clinical efficacy of the proteasomal inhibition is limited in solid cancers. Interestingly, recent studies show that the ubiquitin-proteasome and epigenetic pathways intersect in a number of ways through the regulation of epigenetic marks (i.e., acetylation, methylation and ubiquitylation).
    CONCLUSION: it is therefore believed that novel treatment strategies involving new generation ubiquitin-proteasome pathway inhibitors combined with DNA methyltransferase, histone deacetylase or histone acetyltransferase inhibitors may produce more effective results with fewer adverse effects in cancer treatment as compared to standard chemotherapeutics in hematological as well as solid cancers.
    Keywords:  Bortezomib; cancer; epigenetics; histone deacetylase; proteasome; ubiquitin
    DOI:  https://doi.org/10.2174/1871520620666200811114159
  2. Cells. 2020 Aug 07. pii: E1850. [Epub ahead of print]9(8):
    DNA Methylation as a Therapeutic Target for Bladder Cancer.
    Sandra P Nunes, Rui Henrique, Carmen Jerónimo, Jesús M Paramio.
      Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted by the current treatment options. Thus, the development of new therapeutic strategies, either alternative or complementary to the current ones, is of major importance. The disruption of normal epigenetic mechanisms, namely, DNA methylation, is a known early event in cancer development. Consequently, DNA methyltransferase (DNMT) inhibitors constitute a promising therapeutic target for the treatment of BC. Although these inhibitors, mainly nucleoside analogues such as 5-azacytidine (5-aza) and decitabine (DAC), cause re-expression of tumor suppressor genes, inhibition of tumor cell growth, and increased apoptosis in BC experimental models and clinical trials, they also show important drawbacks that prevent their use as a valuable option for the treatment of BC. However, their combination with chemotherapy and/or immune-checkpoint inhibitors could aid in their implementation in the clinical practice. Here, we provide a comprehensive review of the studies exploring the effects of DNA methylation inhibition using DNMTs inhibitors in BC, from in vitro and in vivo studies to clinical trials.
    Keywords:  DNA methylation; DNA methyltransferases; bladder cancer; nucleoside analogues; therapy
    DOI:  https://doi.org/10.3390/cells9081850
  3. Nat Rev Cancer. 2020 Aug 11.
    The epigenomics of sarcoma.
    Benjamin A Nacev, Kevin B Jones, Andrew M Intlekofer, Jamie S E Yu, C David Allis, William D Tap, Marc Ladanyi, Torsten O Nielsen.
      Epigenetic regulation is critical to physiological control of development, cell fate, cell proliferation, genomic integrity and, fundamentally, transcriptional regulation. This epigenetic control occurs at multiple levels including through DNA methylation, histone modification, nucleosome remodelling and modulation of the 3D chromatin structure. Alterations in genes that encode chromatin regulators are common among mesenchymal neoplasms, a collection of more than 160 tumour types including over 60 malignant variants (sarcomas) that have unique and varied genetic, biological and clinical characteristics. Herein, we review those sarcomas in which chromatin pathway alterations drive disease biology. Specifically, we emphasize examples of dysregulation of each level of epigenetic control though mechanisms that include alterations in metabolic enzymes that regulate DNA methylation and histone post-translational modifications, mutations in histone genes, subunit loss or fusions in chromatin remodelling and modifying complexes, and disruption of higher-order chromatin structure. Epigenetic mechanisms of tumorigenesis have been implicated in mesenchymal tumours ranging from chondroblastoma and giant cell tumour of bone to chondrosarcoma, malignant peripheral nerve sheath tumour, synovial sarcoma, epithelioid sarcoma and Ewing sarcoma - all diseases that present in a younger patient population than most cancers. Finally, we review current and potential future approaches for the development of sarcoma therapies based on this emerging understanding of chromatin dysregulation.
    DOI:  https://doi.org/10.1038/s41568-020-0288-4
  4. J Med Chem. 2020 Aug 11.
    Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases.
    Kaikai Lv, Weicong Chen, Danqi Chen, Jie Mou, Huijie Zhang, Tiantian Fan, Yanlian Li, Danyan Cao, Xin Wang, Lin Chen, Jingkang Shen, Dongsheng Pei, Bing Xiong.
      Cancer exhibits diverse heterogeneity with a complicated molecular basis that usually harbors genetic and epigenetic abnormality, which poses a big challenge for single-target agents. In the current work, we proposed a hybrid strategy by incorporating pharmacophores that bind to the acetylated lysine binding pocket of BET proteins with typical kinases hinge binder to generate novel polypharmacological inhibitors of BET and kinases. Through elaborating the core structure of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-one, we demonstrated that this rational design can produce high potent inhibitors of CDK9 and BET proteins.In this series, compound 40 was identified as the potential lead compound with balanced activities of BRD4 (IC50=12.7 nM) and CDK9 (IC50=22.4 nM), as well as good antiproliferative activities on a small cancer cell panel. Together, current study provided a new method for the discovery of bromodomain and kinases dual inhibitors rather than only discovered by serendipity.
    DOI:  https://doi.org/10.1021/acs.jmedchem.0c00962
  5. J Enzyme Inhib Med Chem. 2020 Dec;35(1): 1606-1615
    Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1).
    Zhimin Zhang, Xinyue Chang, Chixiao Zhang, Shenxin Zeng, Meihao Liang, Zhen Ma, Zunyuan Wang, Wenhai Huang, Zhengrong Shen.
      Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.
    Keywords:  PARP-1; PROTAC; target protein knockdown
    DOI:  https://doi.org/10.1080/14756366.2020.1804382
  6. Cell Discov. 2020 ;6 49
    A triple action CDK4/6-PI3K-BET inhibitor with augmented cancer cell cytotoxicity.
    Adam M Burgoyne, Kendra R Vann, Shweta Joshi, Guillermo A Morales, Francisco M Vega, Alok Singh, Dhananjaya Pal, Aran B Merati, Tatiana G Kutateladze, Donald L Durden.
      
    Keywords:  Cancer therapy; Epigenetics; X-ray crystallography
    DOI:  https://doi.org/10.1038/s41421-020-0181-z
  7. Sci Adv. 2020 Jul;6(31): eaay9131
    Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells.
    Seung Ho Shin, Ji Su Lee, Jia-Min Zhang, Sungbin Choi, Zarko V Boskovic, Ran Zhao, Mengqiu Song, Rui Wang, Jie Tian, Mee-Hyun Lee, Jae Hwan Kim, Minju Jeong, Jung Hyun Lee, Michael Petukhov, Sam W Lee, Sang Gyun Kim, Lee Zou, Sanguine Byun.
      Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.
    DOI:  https://doi.org/10.1126/sciadv.aay9131
  8. Life Sci. 2020 Aug 06. pii: S0024-3205(20)30963-2. [Epub ahead of print]258 118211
    Flavonoids potentiated anticancer activity of cisplatin in non-small cell lung cancer cells in vitro by inhibiting histone deacetylases.
    Wei Yan, Tracy H Y Wu, Sharon S Y Leung, Kenneth K W To.
      AIMS: Cisplatin is the mainstay of first-line treatment for advanced non-small cell lung cancer (NSCLC). Accumulating evidence suggests that flavonoids inhibit histone deacetylase (HDAC) to mediate their anticancer effect in various cancer types. The study was conducted to investigate the inhibition of HDAC and the modulation of apoptotic and cell cycle regulatory genes by selected flavonoids to potentiate the anticancer effect of cisplatin.MAIN METHODS: Combinations of cisplatin and selected flavonoids were investigated in three NSCLC cell lines (A549, H460, and H1299). Sulforhodamine B assay was used to evaluate cytotoxicity of drug combinations. Western blot analysis was conducted to evaluate histone acetylation. Flow cytometric assays were used to investigate the apoptotic and cell cycle effect. Chromatin immunoprecipitation assay was performed to elucidate the binding of transcription factors to promoters of selected apoptotic and cell cycle regulatory genes.
    KEY FINDINGS: Apigenin was found to exhibit the strongest HDAC inhibitory effect among all flavonoids tested. Cisplatin-apigenin combination was shown to produce significantly more S phase prolongation and G2/M cell cycle arrest, and apoptosis compared with cisplatin or apigenin alone, by inducing p21 and PUMA, respectively. More pronounced effect was observed in p53-proficient than p53-null NSCLC cells. Mechanistically, apigenin was found to reduce the binding of HDAC1 but increase the association of RNA polymerase II and Sp1 to p21 and PUMA promoters.
    SIGNIFICANCE: Our findings provide a better insight about the mechanism contributing to the HDAC inhibitory effect of apigenin to potentiate anticancer effect of cisplatin by inducing apoptosis and cell cycle arrest.
    Keywords:  Apigenin; Cisplatin; Histone deacetylases; Non-small cell lung cancer
    DOI:  https://doi.org/10.1016/j.lfs.2020.118211
  9. Drug Discov Today. 2020 Aug 06. pii: S1359-6446(20)30301-9. [Epub ahead of print]
    Myeloid cell leukemin-1 inhibitors: a growing arsenal for cancer therapy.
    Peng-Ju Zhu, Ze-Zhou Yu, Qi-Dong You, Zheng-Yu Jiang.
      B-cell lymphoma-2 (Bcl-2) family proteins, comprising proapoptotic proteins (Bax and Bak), antiapoptotic proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and A1) and BCL-2 homology domain 3 (BH3)-only proteins (Bid, Noxa, and Puma), have long been identified as pivotal apoptosis regulators. As an antiapoptotic member, myeloid cell leukemin-1 (Mcl-1) can bind with proapoptotic proteins and inhibit apoptosis. Mcl-1 is frequently overexpressed and closely associated with oncogenesis and poor prognosis in several cancers, posing a tremendous obstacle for cancer therapy. Recently, an increasing number of Mcl-1-selective small-molecule inhibitors have entered preclinical studies and advanced into clinical trials. In this review, we briefly introduce the role of Mcl-1 in apoptosis and highlight the recent development of Mcl-1 small-molecule inhibitors.
    DOI:  https://doi.org/10.1016/j.drudis.2020.07.021
  10. Nat Chem Biol. 2020 Aug 10.
    Functional characterization of a PROTAC directed against BRAF mutant V600E.
    Ganna Posternak, Xiaojing Tang, Pierre Maisonneuve, Ting Jin, Hugo Lavoie, Salima Daou, Stephen Orlicky, Theo Goullet de Rugy, Lauren Caldwell, Kin Chan, Ahmed Aman, Michael Prakesch, Gennady Poda, Pavel Mader, Cassandra Wong, Stefan Maier, Julia Kitaygorodsky, Brett Larsen, Karen Colwill, Zhe Yin, Derek F Ceccarelli, Robert A Batey, Mikko Taipale, Igor Kurinov, David Uehling, Jeff Wrana, Daniel Durocher, Anne-Claude Gingras, Rima Al-Awar, Marc Therrien, Frank Sicheri.
      The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation and survival, enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAF(V600E) have shown great efficacy in the clinic, but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis-targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC, termed P4B, displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAF(V600E) cell lines. In addition, P4B displayed utility in cell lines harboring alternative BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a proof of concept for a substitute to conventional chemical inhibition to therapeutically constrain oncogenic BRAF.
    DOI:  https://doi.org/10.1038/s41589-020-0609-7
  11. Eur J Med Chem. 2020 Jul 26. pii: S0223-5234(20)30620-6. [Epub ahead of print]205 112648
    Design, synthesis and biological evaluation of novel HDAC inhibitors with improved pharmacokinetic profile in breast cancer.
    Dahong Yao, Chenyang Li, Jin Jiang, Jian Huang, Jinhui Wang, Zhendan He, Jin Zhang.
      The dysfunction of histone deacetylase (HDACs) is closely related to tumorigenesis and development, which has been emerged as an attractive drug design target for cancer therapy. In the present study, we designed and synthesized a series of novel HDAC inhibitors using a substituted quinazoline as the capping group and attaching 3, 5-dimethylbenyl as a potential metabolic site protector. 23g and 23h were demonstrated potent HDAC inhibitory activities and anti-proliferative effects against MDA-MB-231 cells. In addition, 23g and 23h both could significantly increase the acetylation level of intracellular proteins, especially in α-Tubulin and HSP90. 23g and 23h displayed a slight different anti-tumor mechanism, 23g mainly induced apoptosis while 23h induced obviously ER-Stress. Furthermore, 23g and 23h both induced autophagy and migration inhibition. In pharmacokinetics assay, 23g showed a significant improvement of pharmacokinetic profile for oral administration. Additionally, 23g presented more potent anti-proliferation and anti-migration activity than SAHA in zebrafish MDA-MB-231 cell line-derived xenograft model. Together, these results demonstrate that 23g is a novel oral HDAC inhibitor with a potential capacity of treating breast cancer.
    Keywords:  Apoptosis; Autophagy; Breast cancer; HDAC inhibitor; Migration; Pharmacokinetic profile
    DOI:  https://doi.org/10.1016/j.ejmech.2020.112648
  12. Nat Commun. 2020 Aug 14. 11(1): 4083
    BRD4 prevents the accumulation of R-loops and protects against transcription-replication collision events and DNA damage.
    Fred C Lam, Yi Wen Kong, Qiuying Huang, Tu-Lan Vu Han, Amanda D Maffa, Ekkehard M Kasper, Michael B Yaffe.
      Proper chromatin function and maintenance of genomic stability depends on spatiotemporal coordination between the transcription and replication machinery. Loss of this coordination can lead to DNA damage from increased transcription-replication collision events. We report that deregulated transcription following BRD4 loss in cancer cells leads to the accumulation of RNA:DNA hybrids (R-loops) and collisions with the replication machinery causing replication stress and DNA damage. Whole genome BRD4 and γH2AX ChIP-Seq with R-loop IP qPCR reveals that BRD4 inhibition leads to accumulation of R-loops and DNA damage at a subset of known BDR4, JMJD6, and CHD4 co-regulated genes. Interference with BRD4 function causes transcriptional downregulation of the DNA damage response protein TopBP1, resulting in failure to activate the ATR-Chk1 pathway despite increased replication stress, leading to apoptotic cell death in S-phase and mitotic catastrophe. These findings demonstrate that inhibition of BRD4 induces transcription-replication conflicts, DNA damage, and cell death in oncogenic cells.
    DOI:  https://doi.org/10.1038/s41467-020-17503-y
  13. Cancer Cell. 2020 Jul 30. pii: S1535-6108(20)30369-X. [Epub ahead of print]
    Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas.
    Chan Chung, Stefan R Sweha, Drew Pratt, Benita Tamrazi, Pooja Panwalkar, Adam Banda, Jill Bayliss, Debra Hawes, Fusheng Yang, Ho-Joon Lee, Mengrou Shan, Marcin Cieslik, Tingting Qin, Christian K Werner, Daniel R Wahl, Costas A Lyssiotis, Zhiguo Bian, J Brad Shotwell, Viveka Nand Yadav, Carl Koschmann, Arul M Chinnaiyan, Stefan Blüml, Alexander R Judkins, Sriram Venneti.
      H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. They mainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysis in H3.3K27M cells, tumors, and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and tricarboxylic acid cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/or glutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition of key enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatin accessibility, and prolonged survival in animal models. Previous studies have shown that mutant isocitrate-dehydrogenase (mIDH)1/2 glioma cells convert α-KG to D-2-hydroxyglutarate (D-2HG) to increase H3K27me3. Here, we show that H3K27M and IDH1 mutations are mutually exclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27M and mIDH1 hijack a conserved and critical metabolic pathway in opposing ways to maintain their preferred epigenetic state. Consequently, interruption of this metabolic/epigenetic pathway showed potent efficacy in preclinical models, suggesting key therapeutic targets for much needed treatments.
    Keywords:  D-2HG; DIPG; H3K27me3; IDH mutation; epigenetics; glutaminolysis; glycolysis; histone methylation; histone mutation; metabolism; α-KG
    DOI:  https://doi.org/10.1016/j.ccell.2020.07.008
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