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Curaxins 2

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Curaxins is a family of carbazole-based small molecules with anti-cancer activity. The first curaxin (CBL000) was discovered in 2003 in a cellular phenotype-based screen designed to identify novel anti-cancer compounds capable of simultaneously activating tumor suppressor p53 and inhibiting pro-survival transcription factor NF-kappaB...[1]. A structure activity relationship study led to the discovery of several additional proprietary curaxin molecules with similar chemical structure, mechanism of action, and biological effects in mammalian cells. These effects include modulation of the activity of multiple transcription factors, several DNA-related enzymes and the histone chaperone FACT [2]. All of these effects appear to stem from the ability of curaxins to bind genomic DNA in cells with high affinity, but without induction of DNA damage [2]. Although curaxin binding does not induce chemical DNA modifications, it does alter the shape, flexibility and electrical charge of the DNA helix. These changes make DNA less capable of wrapping around histones to form nucleosomes, the basic units of chromatin. This leads to the loss of histones from chromatin in curaxin-treated cells and numerous downstream effects on gene expression and DNA metabolism that impact cell growth and survival [3]. Thus, analogous to DNA damaging drugs, curaxins have been classified as “chromatin damaging” agents. In fact, induction of chromatin damage in the absence of DNA damage was first proposed as a promising anti-cancer approach based on the mechanism of action and biological activity of curaxins [4]. Curaxins have demonstrated anti-tumor activity in a wide range of animal tumor models. The lead curaxin CBL0137 is currently being tested in several clinical studies against solid and hematological malignancies. [5][6]

Chemistry[edit]

Curaxins are carbazole derivatives typically with acyl substituents at positions 3- and 6- of the carbazole, and an N-linker containing a secondary or tertiary amino group that is separated by 2-to-4 carbon atoms from the carbazole nitrogen. The 3D superimposition of conformers of carbazole derivatives active and inactive in p53 activation assay revealed some characteristics of the compounds that lead to their activity as p53 activators. The most important characteristic is the planarity of the carbazole core with substituents at positions 3- and 6-. Comparing multiple 3D alignments of the conformers, it was found that in all active compounds (curaxins) the carbazole core region was strictly planar. Inactive compounds could be planar or non-planar. Superposition of the conformers of active and inactive carbazole derivatives also revealed that in active molecules (curaxins) the conformation on N-linker is more uniform. This uniformity facilitates its alignment along the small groove of DNA. The combination of effective intercalation of carbazole core with proper alignment of N-linker along minor groove of DNA enhances the stability of curaxin-DNA non-covalent complex and is crucial for biological activity of curaxins.

History of discovery[edit]

The prototype curaxin CBL000 was identified in a cellular phenotype-based screening designed to find synthetic small molecules able to activate tumor suppressor p53 via mechanisms not involving induction of DNA damage. This screening was performed in the laboratory of Andrei Gudkov at the Cleveland Clinic. Kidney cancer cell line, RCC45, provided an ideal readout system for identification of p53 activators with novel mechanisms of action because it express p53 that is wild type but cannot be activated by DNA damage[7]. The top hits identified in the screening belong to two chemical classes, 9-aminoacridines and carbazoles. Since several known drugs are aminoacridines, Gudkov’s team decided to look for DNA damage-independent p53 activators among those already in clinical use with established safety profiles. Interestingly, among known aminoacridines, the anti-malarial compound quinacrine induced p53 activation in RCC45 cells, while the anti-cancer DNA damaging drug amsacrine was inactive. This provided validation of the rationale underlying the design of the RCC45-based screen and suggested that hit compounds most likely did indeed activate p53 via DNA damage-independent mechanisms. In further testing, quinacrine demonstrated potent activity against a variety of different tumor cell lines. It was more toxic for tumor, than normal cells. Moreover, it was less, but also toxic to tumor cells with no functional p53[1]. The latter finding suggested that quinacrine must affect additional, non-p53-related pathways critical for cell survival.
Investigation of the mechanism by which quinacrine activates p53 by a team led by Katerina Gurova in the Gudkov lab among other possibilities tested whether quinacrine inhibits protein degradation since this might explain the observed stabilization of p53. Fortuitously, use of I-kappaB alpha as a control substrate of proteasome-mediated degradation in these experiments led to the discovery that quinacrine is an inhibitor of NF-kappaB, a transcription factor that controls expression of I-kappaB and many other genes involved in numerous cellular and organismal processes, including inflammation, apoptosis and tumor development and progression. Thus, quinacrine was shown to have dual, seemingly unrelated activity toward two transcription factors with critical roles in tumors: activation of p53 and inhibition of NF-kappaB[1]. Such activity is expected to counteract tumor growth and survival since multiple tumors are characterized by loss of p53 function and/or constitutive activation of NF-kappaB. Mutually antagonistic interactions of NF-kappaB and p53 in tumors including inhibition of p53 by overactive NF-kappaB have been proposed to explain how inflammation predisposes to cancer and why p53 may remain unaltered in tumors with high basal activity of NF-kappaB [8]. Overall, the finding that quinacrine modulated the activity of both p53 and NF-kappaB in the desired directions to suppress tumor growth revealed it as a “double-edged sword” with strong potential as a multi-targeted anti-cancer agent.
Based on the findings described above, clinical development of quinacrine as an anti-cancer agent was initiated by Cleveland BioLabs, Inc., founded by Andrei Gudkov. The safety profile of quinacrine was already well established due to its use as an anti-malarial agent in millions of American soldiers based in Pacific regions during and after World War II. Moreover, prior to the introduction of cortisone, quinacrine was empirically identified and widely used as a treatment for auto-immune diseases, particularly those involving skin lesions (e.g., lupus)[9]. Interestingly, quinacrine never got FDA approval, since its clinical use started before FDA was formed. The effectiveness of quinacrine in patients with auto-immune diseases is likely explained by the recently discovered NF-kappaB inhibiting activity of the drug. However, despite its favorable effects in several diseases, a number of pharmacological characteristics of quinacrine have limited its clinical usefulness overall and development as an anti-cancer agent in particular. These include (i) its peculiar biodistribution (quinacrine accumulates to very high levels in skin and liver with exposure in other organs only starting after skin and liver are saturated), (ii) its bright yellow color. Accumulation of quinacrine in the skin causes yellow discoloration which is disliked by both physicians concerned of jaundice and patients. (iii) The practical difficulties associated with rapid loading of patients with quinacrine since above certain blood concentrations it penetrates the blood-brain barrier and causes psychosis similar to strong alcohol intoxication. The latter characteristic means that patients receiving high doses of quinacrine must be constrained until the drug is cleared from the brain (1-2 days). At reasonable doses that do not lead to brain exposure, saturation of the liver and skin occurs only after 6-8 weeks of quinacrine administration, which is considered acceptable for patients with auto-immune skin lesions, but not for those with cancer. Nevertheless, quinacrine is still considered as a liver cancer treatment (especially in less developed countries) due to its potential efficacy and low price.
Given the known limitations of quinacrine, Cleveland BioLab’s team performed several additional screenings to identify new compounds sharing the dual activity observed for quinacrine: simultaneous activation of p53 (without induction of DNA damage) and inhibition of NF-kappaB. Most of the hits identified in the new screens were again 9-aminoacridines and carbazoles, with the latter class being generally more active than the former. Most of the carbazoles were colorless; were distributed more or less evenly throughout the body; lack some undesirable activities of quinacrine (e.g. inhibition of acetylcholine receptor, most probably responsible for brain toxicity[9]). Therefore, the main focus of further development efforts was placed on carbazoles. Active compounds of this chemical class were named curaxins, from “cure”[2].

Mechanism of action[edit]

Current understanding of the mechanism of action of curaxins is that the biological effects of these compounds stem from their ability to bind genomic DNA in cells, which results in chromatin disassembly but not chemical DNA damage[2], [3]. DNA is a flexible double helical polymer that has certain parameters under physiological conditions in cells that are critical for its biological function; these include its shape (length, width, degree of twisting), flexibility, and negative electrical charge. Curaxins binding to DNA does not cause any detectable chemical DNA modifications (i.e., breaks or nucleotide alterations). However, it does change the shape of the DNA molecule (increases its length due to intercalation of curaxin molecules between base pairs), reduce its flexibility, and diminish its negative charge (since curaxins are positively charged). While DNA can tolerate all of these changes without undergoing any disintegration, the basic units of chromatin, nucleosomes, cannot.
A nucleosome consists of a positively charged central protein octamer around which 146-147 base pairs of genomic DNA is wrapped ~1.7 times [10]. The exceptional stability of nucleosomes is provided by (i) electrostatic attraction between positively charged histone proteins and negatively charged DNA, (ii) multiple point contacts between amino acids of histone proteins and DNA, with specific amino acid side chains intercalating between DNA base pairs or filling the minor groove, and (iii) the perfect fit of the DNA helix around the histone core based on the flexibility of DNA and the diameter of the histone octamer[10]. Curaxin binding to DNA disturbs each of these aspects of nucleosome stability, reducing the negative charge of DNA, interfering with contacts between histone amino acids and DNA, and making DNA more rigid and less able to wrap around histone octamers tightly. Indeed, curaxin-induced nucleosome destabilization and disassembly has been observed both in cells and under cell-free conditions[3], leading curaxins to be defined as chromatin-damaging agents.

Biological activity[edit]

Curaxins cause the following effects in cells:

Destabilization of chromatin[edit]

At low doses, curaxins cause loss of linker histone H1 from chromatin and “opening” of nucleosomes. At higher concentrations, unwrapping of nucleosomal DNA occurs and leads to the loss of outer histones H2A and H2B from chromatin. Finally, at even higher curaxin concentrations, inner histones H3 and H4 leave chromatin. It is currently unclear whether chromatin in cells can be completely disassembled following curaxin treatment or if histone loss occurs only at certain genomic regions. The consequences of chromatin destabilization in cells are not well studied, but depending of the degree of destabilization, the following are observed: (i) appearance of free histones; (ii) desilencing of heterochromatin and emergence of pervasive transcription; and (iii) disturbance of long-range chromatin interactions and corresponding regulatory mechanisms.

Inhibition of nucleases[edit]

Many nucleases, including topoisomerases, cannot cleave DNA in the presence of curaxins. This distinguishes curaxins from many other DNA binding molecules, which only inhibit the religation activity of topoisomerases, not their cleavage activity. Inhibition of nucleases, including micrococcal nuclease which is frequently used to assess chromatin organization in cells, is known property of DNA-binding small molecules [11].

C-trapping of FACT[edit]

FACT (Facilitates Chromatin Transcription) is a histone chaperone that is involved in multiple chromatin-related processes, such as transcription, replication and DNA repair. It binds components of nucleosomes (histone dimers and DNA) via different domains of its two subunits, SSRP1 and SPT16, thereby controlling nucleosome accessibility and stability. In curaxin-treated cells, destabilization of nucleosomes exposes multiple sites for FACT binding that are normally hidden within assembled nucleosomes[2], [3]. This leads to FACT becoming tightly bound in chromatin (referred to as chromatin-trapping, or c-trapping) and depleted from regions of active transcription, and probably from replication sites, where it is enriched under basal conditions. The redistribution of FACT in curaxin-treated cells thus results in its functional inhibition. Notably, FACT levels are elevated in various types of tumors and correlate with poor prognosis [12], [13], [14], providing a mechanistic explanation for the observed anti-cancer activity of curaxins.

Activation of tumor suppressor p53[edit]

While curaxins were discovered based on their ability to cause p53 activation, exactly how they do this remains unclear. The two most likely mechanisms are: (i) When FACT is trapped in chromatin, FACT-associated casein kinase 2 phosphorylates p53 at serine 392 (no other phosphorylated sites were found in p53 in curaxin-treated cells)[2], [15], [16]and (ii) histones lost from chromatin in curaxin-treated cells accumulate in the nucleolus [3] and this organelle is known to contain proteins that bind and inactivate MDM2, a major negative regulator of p53, upon nucleolar disintegration (“nucleolar stress”) [17], [18]. Therefore, accumulation of histones in nucleoli may be responsible for nucleolar stress and inhibition of MDM2 leading to stabilization of p53. While p53 in curaxin-treated cells lacks the post-translational modifications characteristic of DNA damage-dependent activation, it is fully functional and capable of transactivation and induction of growth arrest or apoptosis.

Induction of type I interferon response[edit]

The type I interferon response is a physiological immune response in mammals that is initiated upon detection of products of viral metabolism (e.g., double stranded RNA) by specific intracellular receptors. Receptor activation leads to synthesis of interferons alpha and beta, which in turn bind their own receptor and stimulate expression of interferon stimulated genes (ISGs) encoding proteins with roles in blocking viral expansion or eliminating infected cells. Destabilization of nucleosomes by curaxins leads to increased accessibility of heterochromatin and desilencing of the various types of repetitive elements it contains (e.g., centromeric or pericentromeric repeats, endogenous retroviruses, etc.). Moreover, transcription of these elements occurs in both directions, thus leading to the emergence of double stranded RNAs capable of inducing a type I interferon response [19]

Dysregulation of transcription[edit]

Curaxin-induced changes in chromatin structure have profound effects on transcription. Some genes, such as those regulated by p53 or ISGs become activated, while many others are inhibited (e.g., MYC and genes regulated by NF-kappaB, HSF1, etc.). While upregulation of p53-regulated genes and ISGs makes sense due to the observed stabilization of p53 and production of interferons in curaxin-treated cells, the mechanisms underlying inhibition of expression of other genes are not completely clear. Possible explanations include disruption of promoter/enhancer interactions or occurrence of pervasive transcription following curaxin binding to DNA. Loss of nucleosomes is a known trigger of transcription initiated from cryptic promoters that are not utilized under basal conditions. While the origins of these cryptic promoters are not completely clear, some of them are remnants of ancient retroviral LTRs [20], that are kept silent by being packaged in heterochromatin. Relaxation of the normal transcriptional controls imposed by chromatin structure results in pervasive, cryptic, and divergent (i.e., proceeding in both sense and anti-sense directions) transcription, all of which may interfere with normal transcription.

Cellular growth arrest[edit]

Growth arrest is observed in cells treated with the relatively low concentrations of curaxins that do not induce significant nucleosome disassembly, but only chromatin opening accompanied by eviction of linker histone H1 and occasional loss of outer histones H2A and H2B. This effect is reversible upon drug removal, especially in normal cells. In tumor cells, continued exposure to curaxins results in transition from growth arrest to cell death.

Cell death[edit]

Cell death is caused by the higher concentrations of curaxins that induce eviction of core histones from chromatin. If cells express wild type p53, curaxin-induced cell death is accompanied by activation of caspases in the cytoplasm similarly to apoptotic cell death. However, the nuclear aspects of cell death induced by curaxins are different from those observed in apoptosis: there is no characteristic chromatin condensation or nuclear fragmentation. This may be due to inhibition of caspase-activated nucleases, which are responsible for DNA cleavage in the case of apoptosis, by curaxins. Cell lacking functional p53 die following curaxin exposure via a caspase-independent mechanism that has not yet been fully studied.

Anti-cancer activity of curaxins[edit]

The clinical lead curaxin, CBL0137, demonstrated significant anti-cancer activity in a number of preclinical tumor models, including colon, pancreatic, prostate and breast adenocarcinomas, melanoma, kidney cancer, glioblastoma, hematological malignancies, and several pediatric malignancies, including neuroblastoma[2], [12], [13] [21], [22], [23]. It showed efficacy both as a monotherapy and in combination with standard of care and various targeted therapies. CBL0137 also demonstrated cancer-preventive activity [24]. To evaluate cancer prevention, CBL0137 was given to mice predisposed to develop breast cancer in their drinking water for almost all their life. CBL0137 reduced the incidence of cancer by more than 50% and did not show any teratogenic effects (i.e., mice drinking water with CBL0137 had normal pregnancies and their pups did not have any malformations). CBL0137 is orally bioavailable (~80% in mice and ~50% in humans) and can be given at low doses daily or at high doses once per week. Maximal efficacy with minimal toxicity is observed upon weekly intravenous injections. In animal studies, significant inhibition of tumor growth, and in some cases complete tumor eradication, was observed at non-toxic concentrations of CBL0137. In animals toxic effects at high concentrations include weight loss and reduction of blood counts (white blood cells and platelets). Local skin irritation and endothelial damage are possible upon injection of concentrated CBL0137 solution intravenously. In ongoing clinical trials, CBL0137 is being tested in two regimens, daily oral administration and once per week intravenous infusion.
A critical aspect of the activity of curaxins that supports their potential use as anti-cancer therapeutics is their greater toxicity towards tumor cells compared to normal cells. While the mechanisms underlying this specificity are not completely clear, there are a number of distinguishing characteristics of tumor cells that likely contribute to their sensitivity to curaxins. These include differences in chromatin organization in tumor versus normal cells and greater dependence of tumor cells than normal cells on curaxin-inhibited pathways including those controlled by FACT and transcription factors such as Myc family members, NF-kappaB, HSF1, HIF1 alpha, etc.

Anti-infective activity[edit]

Several curaxin molecules (named xenomycins) were tested against malaria[25]. They were toxic to the malaria parasite, Plasmodium falciparum, in vitro. Oral administration of xenomycins in mouse models of malaria resulted in effective clearance of liver and blood asexual and sexual stages, as well as effective inhibition of transmission to mosquitoes. These characteristics position xenomycins as antimalarial candidates with potential activity in prevention, treatment and elimination of this disease. As for quinacrine, mechanism of anti-malarial activity of curaxins is not known yet, although it was shown that FACT, which is inhibited by curaxins, is critical for viability of Plasmodium berghei [26]
Curaxins also showed anti-viral activity. They block HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional Elongation[27]. In models of lytic and latent replication of human cytomegalovirus, they reduced transcription from the cytomegalovirus major immediate early promoter [28]

References[edit]

  1. 1.0 1.1 1.2 K.V. Gurova, J.E. Hill, C. Guo, A. Prokvolit, L.G. Burdelya, E. Samoylova, A.V. Khodyakova, R. Ganapathi, M. Ganapathi, N.D. Tararova, D. Bosykh, D. Lvovskiy, T.R. Webb, G.R. Stark, A.V. Gudkov, Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappaB-dependent mechanism of p53 suppression in tumors, Proc Natl Acad Sci U S A, 102 (2005) 17448-17453.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 A.V. Gasparian, C.A. Burkhart, A.A. Purmal, L. Brodsky, M. Pal, M. Saranadasa, D.A. Bosykh, M. Commane, O.A. Guryanova, S. Pal, A. Safina, S. Sviridov, I.E. Koman, J. Veith, A.A. Komar, A.V. Gudkov, K.V. Gurova, Curaxins: anticancer compounds that simultaneously suppress NF-kappaB and activate p53 by targeting FACT, Sci Transl Med, 3 (2011) 95ra74.
  3. 3.0 3.1 3.2 3.3 3.4 A. Safina, P. Cheney, M. Pal, L. Brodsky, A. Ivanov, K. Kirsanov, E. Lesovaya, D. Naberezhnov, E. Nesher, I. Koman, D. Wang, J. Wang, M. Yakubovskaya, D. Winkler, K. Gurova, FACT is a sensor of DNA torsional stress in eukaryotic cells, Nucleic Acids Res, 45 (2017) 1925-1945.
  4. E. Nesher, A. Safina, I. Aljahdali, S. Portwood, E.S. Wang, I. Koman, J. Wang, K.V. Gurova, Role of chromatin damage and chromatin trapping of FACT in mediating the anticancer cytotoxicity of DNA-binding small molecule drugs, Cancer Res, (2018).
  5. "A Phase 1 Trial of CBL0137 in Patients With Metastatic or Unresectable Advanced Solid Neoplasm - Full Text View - ClinicalTrials.gov".
  6. "Study of IV CBL0137 in Previously Treated Hematological Subjects - Full Text View - ClinicalTrials.gov".
  7. K.V. Gurova, J.E. Hill, O.V. Razorenova, P.M. Chumakov, A.V. Gudkov, p53 pathway in renal cell carcinoma is repressed by a dominant mechanism, Cancer Res, 64 (2004) 1951-1958.
  8. A.V. Gudkov, K.V. Gurova, E.A. Komarova, Inflammation and p53: A Tale of Two Stresses, Genes Cancer, 2 (2011) 503-516.
  9. 9.0 9.1 K. Gurova, New hopes from old drugs: revisiting DNA-binding small molecules as anticancer agents, Future Oncol, 5 (2009) 1685-1704.
  10. 10.0 10.1 K. Luger, A.W. Mader, R.K. Richmond, D.F. Sargent, T.J. Richmond, Crystal structure of the nucleosome core particle at 2.8 A resolution, Nature, 389 (1997) 251-260.
  11. A.S. Biebricher, I. Heller, R.F. Roijmans, T.P. Hoekstra, E.J. Peterman, G.J. Wuite, The impact of DNA intercalators on DNA and DNA-processing enzymes elucidated through force-dependent binding kinetics, Nat Commun, 6 (2015) 7304.
  12. 12.0 12.1 D.R. Carter, J. Murray, B.B. Cheung, L. Gamble, J. Koach, J. Tsang, S. Sutton, H. Kalla, S. Syed, A.J. Gifford, N. Issaeva, A. Biktasova, B. Atmadibrata, Y. Sun, N. Sokolowski, D. Ling, P.Y. Kim, H. Webber, A. Clark, M. Ruhle, B. Liu, A. Oberthuer, M. Fischer, J. Byrne, F. Saletta, M. Thwe le, A. Purmal, G. Haderski, C. Burkhart, F. Speleman, K. De Preter, A. Beckers, D.S. Ziegler, T. Liu, K.V. Gurova, A.V. Gudkov, M.D. Norris, M. Haber, G.M. Marshall, Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma, Sci Transl Med, 7 (2015) 312ra176.
  13. 13.0 13.1 J.K. Dermawan, M. Hitomi, D.J. Silver, Q. Wu, P. Sandlesh, A.E. Sloan, A.A. Purmal, K.V. Gurova, J.N. Rich, J.D. Lathia, G.R. Stark, M. Venere, Pharmacological Targeting of the Histone Chaperone Complex FACT Preferentially Eliminates Glioblastoma Stem Cells and Prolongs Survival in Preclinical Models, Cancer Res, 76 (2016) 2432-2442.
  14. H. Garcia, J.C. Miecznikowski, A. Safina, M. Commane, A. Ruusulehto, S. Kilpinen, R.W. Leach, K. Attwood, Y. Li, S. Degan, A.R. Omilian, O. Guryanova, O. Papantonopoulou, J. Wang, M. Buck, S. Liu, C. Morrison, K.V. Gurova, Facilitates chromatin transcription complex is an "accelerator" of tumor transformation and potential marker and target of aggressive cancers, Cell Rep, 4 (2013) 159-173.
  15. D.M. Keller, H. Lu, p53 serine 392 phosphorylation increases after UV through induction of the assembly of the CK2.hSPT16.SSRP1 complex, J Biol Chem, 277 (2002) 50206-50213.
  16. D.M. Keller, X. Zeng, Y. Wang, Q.H. Zhang, M. Kapoor, H. Shu, R. Goodman, G. Lozano, Y. Zhao, H. Lu, A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1, Mol Cell, 7 (2001) 283-292.
  17. A. James, Y. Wang, H. Raje, R. Rosby, P. DiMario, Nucleolar stress with and without p53, Nucleus, 5 (2014) 402-426.
  18. A. Jin, K. Itahana, K. O'Keefe, Y. Zhang, Inhibition of HDM2 and activation of p53 by ribosomal protein L23, Mol Cell Biol, 24 (2004) 7669-7680.
  19. K. Leonova, A. Safina, E. Nesher, P. Sandlesh, R. Pratt, C. Burkhart, B. Lipchick, I. Gitlin, C. Frangou, I. Koman, J. Wang, K. Kirsanov, M.G. Yakubovskaya, A.V. Gudkov, K. Gurova, TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells, Elife, 7 (2018).
  20. D. Brocks, C.R. Schmidt, M. Daskalakis, H.S. Jang, N.M. Shah, D. Li, J. Li, B. Zhang, Y. Hou, S. Laudato, D.B. Lipka, J. Schott, H. Bierhoff, Y. Assenov, M. Helf, A. Ressnerova, M.S. Islam, A.M. Lindroth, S. Haas, M. Essers, C.D. Imbusch, B. Brors, I. Oehme, O. Witt, M. Lubbert, J.P. Mallm, K. Rippe, R. Will, D. Weichenhan, G. Stoecklin, C. Gerhauser, C.C. Oakes, T. Wang, C. Plass, DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats, Nat Genet, 49 (2017) 1052-1060.
  21. T.A. Barone, C.A. Burkhart, A. Safina, G. Haderski, K.V. Gurova, A.A. Purmal, A.V. Gudkov, R.J. Plunkett, Anticancer drug candidate CBL0137, which inhibits histone chaperone FACT, is efficacious in preclinical orthotopic models of temozolomide-responsive and -resistant glioblastoma, Neuro Oncol, 19 (2017) 186-196.
  22. . Burkhart, D. Fleyshman, R. Kohrn, M. Commane, J. Garrigan, V. Kurbatov, I. Toshkov, R. Ramachandran, L. Martello, K.V. Gurova, Curaxin CBL0137 eradicates drug resistant cancer stem cells and potentiates efficacy of gemcitabine in preclinical models of pancreatic cancer, Oncotarget, 5 (2014) 11038-11053.
  23. M. Kim, N. Neznanov, C.D. Wilfong, D.I. Fleyshman, A.A. Purmal, G. Haderski, P. Stanhope-Baker, C.A. Burkhart, K.V. Gurova, A.V. Gudkov, J.J. Skitzki, Preclinical Validation of a Single-Treatment Infusion Modality That Can Eradicate Extremity Melanomas, Cancer Res, 76 (2016) 6620-6630.
  24. I.E. Koman, M. Commane, G. Paszkiewicz, B. Hoonjan, S. Pal, A. Safina, I. Toshkov, A.A. Purmal, D. Wang, S. Liu, C. Morrison, A.V. Gudkov, K.V. Gurova, Targeting FACT complex suppresses mammary tumorigenesis in Her2/neu transgenic mice, Cancer Prev Res (Phila), 5 (2012) 1025-1035.
  25. J. Erath, J. Gallego-Delgado, W. Xu, G. Andriani, S. Tanghe, K.V. Gurova, A. Gudkov, A. Purmal, E. Rydkina, A. Rodriguez, Small-molecule xenomycins inhibit all stages of the Plasmodium life cycle, Antimicrob Agents Chemother, 59 (2015) 1427-1434.
  26. E.C. Laurentino, S. Taylor, G.R. Mair, E. Lasonder, R. Bartfai, H.G. Stunnenberg, H. Kroeze, J. Ramesar, B. Franke-Fayard, S.M. Khan, C.J. Janse, A.P. Waters, Experimentally controlled downregulation of the histone chaperone FACT in Plasmodium berghei reveals that it is critical to male gamete fertility, Cell Microbiol, 13 (2011) 1956-1974.
  27. M.J. Jean, T. Hayashi, H. Huang, J. Brennan, S. Simpson, A. Purmal, K. Gurova, M.C. Keefer, J.J. Kobie, N.G. Santoso, J. Zhu, Curaxin CBL0100 Blocks HIV-1 Replication and Reactivation through Inhibition of Viral Transcriptional Elongation, Front Microbiol, 8 (2017) 2007.
  28. C.M. O'Connor, M. Nukui, K.V. Gurova, E.A. Murphy, Inhibition of the FACT Complex Reduces Transcription from the Human Cytomegalovirus Major Immediate Early Promoter in Models of Lytic and Latent Replication, J Virol, 90 (2016) 4249-4253.


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