- Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts
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We have developed new, simple, and efficient procedures for the synthesis of two promising histone deacetylase inhibitors (HDIs), CI-994, (N-(2-aminophenyl)-4-acetylaminobenzamide), and MS-275 (N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxycarbonyl)aminomethyl]benzamide) from commercially available acetamidobenzoic acid and 3-(hydroxymethyl)pyridine, respectively. The procedures provide CI-994 and MS-275 in 80% and 72% overall yields, respectively. We found that the combination of four HDIs (CI-994, MS-275, SAHA, and TSA) with retinoids all-trans-retinoic acid (ATRA) or 13-cis-retinoic acid (13-CRA) or our atypical retinoic acid metabolism blocking agents (RAMBAs) 1 (VN/14-1) or 2 (VN/66-1) produced synergistic anti-neoplastic activity on human LNCaP prostate cancer cells. The combination of 2 and SAHA induced G1 and G2/M cell cycle arrest and a decrease in the S phase in LNCaP cells. 2 + SAHA treatment effectively down-regulated cyclin D1 and cdk4, and up-regulated pro-differentiation markers cytokeratins 8/18 and pro-apoptotic Bad and Bax. Following subcutaneous administration, 2, SAHA or 2 + SAHA were well tolerated and caused significant suppression/regression of tumor growth compared with control. These results demonstrate that compound 2 and its combination with SAHA are potentially useful agents that warrant further preclinical development for treatment of prostate cancer.
- Gediya, Lalji K.,Belosay, Aashvini,Khandelwal, Aakanksha,Purushottamachar, Puranik,Njar, Vincent C.O.
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Read Online
- HDAC DEGRADER
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The disclosure provides compounds of formula (I). The compounds may be used to degrade the Histone Deacetylase (HDAC) family of enzymes, particularly HDAC1, 2 and 3 that exist in corepressor complexes. Accordingly, the compounds may
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- PROTAC-mediated degradation of class i histone deacetylase enzymes in corepressor complexes
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We have identified a proteolysis targeting chimera (PROTAC) of class I HDACs 1, 2 and 3. The most active degrader consists of a benzamide HDAC inhibitor, an alkyl linker, and the von Hippel-Lindau E3 ligand. Our PROTAC increased histone acetylation levels and compromised colon cancer HCT116 cell viability, establishing a degradation strategy as an alternative to class I HDAC inhibition.
- Adams, Grace E.,Cowley, Shaun Michael,Hodgkinson, James T.,Millard, Christopher J.,Norris, James K. S.,Schwabe, John W. R.,Smalley, Joshua P.,Song, Yun
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p. 4476 - 4479
(2020/05/13)
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- NOVEL SOLID FORMS OF TACEDINALINE
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Novel solid forms of tacedinaline (4-(acetylamino)-N-(2-aminophenyl)benzamide), including crystalline tacedinaline Forms A, B, and D, a novel crystalline tacedinaline TFA salt, and amorphous tacedinaline, are disclosed. Pharmaceutical compositions comprising crystalline tacedinaline Forms A, B, and D, the novel crystalline tacedinaline TFA salt, and/or amorphous tacedinaline, and methods of treating various conditions by administering those novel solid forms, are also disclosed.
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Paragraph 0127; 0128; 0129
(2013/05/08)
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- NOVEL SOLID FORMS OF TACEDINALINE
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Novel solid forms of tacedinaline (4-(acetylamino)-N-(2-aminophenyl)benzamide), including crystalline tacedinaline Forms A, B, and D, a novel crystalline tacedinaline TFA salt, and amorphous tacedinaline, are disclosed. Pharmaceutical compositions comprising crystalline tacedinaline Forms A, B, and D, the novel crystalline tacedinaline TFA salt, and/or amorphous tacedinaline, and methods of treating various conditions by administering those novel solid forms, are also disclosed.
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Page/Page column 52-53
(2012/01/15)
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- THE USE OF CI-994 AND DINALINE FOR THE TREATMENT OF MEMORY/COGNITION AND ANXIETY DISORDERS
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The invention relates to methods and compositions for promoting cognitive function and/or treating cognitive function disorders and impairments. In particular the methods are accomplished by administering to a subject CI-994 or dinaline or a pharmaceutically acceptable salt, ester, prodrug or metabolite thereof.
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Page/Page column 51; 52
(2011/05/11)
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- Synthesis and biological evaluation of glucuronide prodrugs of the histone deacetylase inhibitor CI-994 for application in selective cancer chemotherapy
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Two glucuronide prodrugs of the histone deacetylase inhibitor CI-994 were synthesized. These compounds were found to be soluble in aqueous media and stable under physiological conditions. The carbamoyl derivatisation of CI-994 significantly decreased its toxicity towards NCI-H661 lung cancer cells. Prodrug incubation with β-glucuronidase in the culture media led efficiently to the release of the parent drug and thereby restoring its ability to decrease cell proliferation, to inhibit HDAC and to induce E-Cadherin expression.
- Thomas, Mickael,Clarhaut, Jonathan,Tranoy-Opalinski, Isabelle,Gesson, Jean-Pierre,Roche, Joelle,Papot, Sebastien
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p. 8109 - 8116
(2008/12/23)
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- Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity
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Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 ? internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis-(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
- Moradei, Oscar M.,Mallais, Tammy C.,Frechette, Sylvie,Paquin, Isabelle,Tessier, Pierre E.,Leit, Silvana M.,Fournel, Marielle,Bonfils, Claire,Trachy-Bourget, Marie-Claude,Liu, Jianhong,Yan, Theresa P.,Lu, Ai-Hua,Rahil, Jubrail,Wang, James,Lefebvre, Sylvain,Li, Zuomei,Vaisburg, Arkadii F.,Besterman, Jeffrey M.
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p. 5543 - 5546
(2008/03/27)
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