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Dacinostat

NVP-LAQ824 inhibits histone deacetylase enzymatic activities in vitro and transcriptionally activated the p21 promoter in reporter gene assays. When tested on a variety of solid tumour cell lines, NVP-LAQ824 exhibited selective anti-proliferative effects, inducing cell growth inhibition in some, while inducing cell death in others. To induce cell death, a minimum of 16 h exposure to NVP-LAQ824 is required. Flow cytometry studies revealed that both tumour cell lines and normal diploid fibroblasts arrested in the G2/M phase of the cell cycle after compound treatment. However, an increased sub-G1 population at 48 h (reminiscent of apoptotic cells) was only observed in the cancer cell lines. Annexin V staining data confirmed that NVP-LAQ824 induced apoptosis in tumour cells, but not in normal cells. To relate HDAC inhibition to the anti-proliferative effects of NVP-LAQ824, expression of HDAC 1 was inhibited using antisense and this was sufficient to activate p21 expression, hypophosphorylate Rb and inhibit cell growth. Furthermore, tumour cells treated with NVP-LAQ824 caused acetylation of HSP90 and degradation of its cargo oncoproteins. Finally, NVP-LAQ824 exhibited antitumour effects in a xenograft animal model. To determine if NVP-LAQ824 inhibited histone deacetylases in vivo, tumours treated with the drug were immunoblotted with an antibody specific for acetylated histones H3 and H4 and the results indicated increased histone H3 and 114 acetylation levels in NVP-LAQ824 treated cancer cells. Together, our data indicated that the activity of NVP-LAQ824 was consistent with its intended mechanism of action. This novel HDAC inhibitor is currently in clinical trials as an anticancer agent. see: http://www.ncbi.nlm.nih.gov/pubmed/15171259.

Current developer: Novartis.

 1: Cho YS, Whitehead L, Li J, Chen CH, Jiang L, Vögtle M, Francotte E, Richert P, Wagner T, Traebert M, Lu Q, Cao X, Dumotier B, Fejzo J, Rajan S, Wang P, Yan-Nea e Y, Shao W, Atadja P, Shultz M. Conformational refinement of hydroxamate-based histone deacetylase inhibitors and exploration of 3-piperidin-3-ylindole analogues of dacinostat (LAQ824). J Med Chem. 2010 Apr 8;53(7):2952-63. PubMed PMID: 20205394.

2: Vo DD, Prins RM, Begley JL, Donahue TR, Morris LF, Bruhn KW, de la Rocha P, Yang MY, Mok S, Garban HJ, Craft N, Economou JS, Marincola FM, Wang E, Ribas A. Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824. Cancer Res. 2009 Nov 15;69(22):8693-9. Epub 2009 Oct 27. PubMed PMID: 19861533; PubMed Central PMCID: PMC2779578.

3: Ellis L, Bots M, Lindemann RK, Bolden JE, Newbold A, Cluse LA, Scott CL, Strasser A, Atadja P, Lowe SW, Johnstone RW. The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy. Blood. 2009 Jul 9;114(2):380-93. Epub 2009 Apr 21. PubMed PMID: 19383971.

4: de Bono JS, Kristeleit R, Tolcher A, Fong P, Pacey S, Karavasilis V, Mita M, Shaw H, Workman P, Kaye S, Rowinsky EK, Aherne W, Atadja P, Scott JW, Patnaik A. Phase I pharmacokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor with a heat shock protein-90 inhibitory profile, in patients with advanced solid tumors. Clin Cancer Res. 2008 Oct 15;14(20):6663-73. PubMed PMID: 18927309.

5: Rosato RR, Almenara JA, Maggio SC, Coe S, Atadja P, Dent P, Grant S. Role of histone deacetylase inhibitor-induced reactive oxygen species and DNA damage in LAQ-824/fludarabine antileukemic interactions. Mol Cancer Ther. 2008 Oct;7(10):3285-97. PubMed PMID: 18852132; PubMed Central PMCID: PMC2586957.

6: Cuneo KC, Fu A, Osusky K, Huamani J, Hallahan DE, Geng L. Histone deacetylase inhibitor NVP-LAQ824 sensitizes human nonsmall cell lung cancer to the cytotoxic effects of ionizing radiation. Anticancer Drugs. 2007 Aug;18(7):793-800. PubMed PMID: 17581301.

7: Kato Y, Salumbides BC, Wang XF, Qian DZ, Williams S, Wei Y, Sanni TB, Atadja P, Pili R. Antitumor effect of the histone deacetylase inhibitor LAQ824 in combination with 13-cis-retinoic acid in human malignant melanoma. Mol Cancer Ther. 2007 Jan;6(1):70-81. PubMed PMID: 17237267.

8: Hurtubise A, Momparler RL. Effect of histone deacetylase inhibitor LAQ824 on antineoplastic action of 5-Aza-2'-deoxycytidine (decitabine) on human breast carcinoma cells. Cancer Chemother Pharmacol. 2006 Nov;58(5):618-25. Epub 2006 Jun 17. PubMed PMID: 16783580.

9: Wang S, Yan-Neale Y, Cai R, Alimov I, Cohen D. Activation of mitochondrial pathway is crucial for tumor selective induction of apoptosis by LAQ824. Cell Cycle. 2006 Aug;5(15):1662-8. Epub 2006 Aug 1. PubMed PMID: 16861932.

10: Rosato RR, Almenara JA, Maggio SC, Atadja P, Craig R, Vrana J, Dent P, Grant S. Potentiation of the lethality of the histone deacetylase inhibitor LAQ824 by the cyclin-dependent kinase inhibitor roscovitine in human leukemia cells. Mol Cancer Ther. 2005 Nov;4(11):1772-85. PubMed PMID: 16275999.

11: Rosato RR, Maggio SC, Almenara JA, Payne SG, Atadja P, Spiegel S, Dent P, Grant S. The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinase-dependent generation of ceramide. Mol Pharmacol. 2006 Jan;69(1):216-25. Epub 2005 Sep 27. PubMed PMID: 16189296.

12: Chen L, Meng S, Wang H, Bali P, Bai W, Li B, Atadja P, Bhalla KN, Wu J. Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824. Mol Cancer Ther. 2005 Sep;4(9):1311-9. PubMed PMID: 16170022.

13: Weisberg E, Catley L, Kujawa J, Atadja P, Remiszewski S, Fuerst P, Cavazza C, Anderson K, Griffin JD. Histone deacetylase inhibitor NVP-LAQ824 has significant activity against myeloid leukemia cells in vitro and in vivo. Leukemia. 2004 Dec;18(12):1951-63. PubMed PMID: 15496979.

14: Grant S. The novel histone deacetylase inhibitor NVP-LAQ824: an addition to the therapeutic armamentarium in leukemia? Leukemia. 2004 Dec;18(12):1931-3. PubMed PMID: 15496978.

15: Qian DZ, Wang X, Kachhap SK, Kato Y, Wei Y, Zhang L, Atadja P, Pili R. The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res. 2004 Sep 15;64(18):6626-34. PubMed PMID: 15374977.

16: Bali P, George P, Cohen P, Tao J, Guo F, Sigua C, Vishvanath A, Scuto A, Annavarapu S, Fiskus W, Moscinski L, Atadja P, Bhalla K. Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin Cancer Res. 2004 Aug 1;10(15):4991-7. PubMed PMID: 15297399.

17: Guo F, Sigua C, Tao J, Bali P, George P, Li Y, Wittmann S, Moscinski L, Atadja P, Bhalla K. Cotreatment with histone deacetylase inhibitor LAQ824 enhances Apo-2L/tumor necrosis factor-related apoptosis inducing ligand-induced death inducing signaling complex activity and apoptosis of human acute leukemia cells. Cancer Res. 2004 Apr 1;64(7):2580-9. PubMed PMID: 15059915.

18: Atadja P, Hsu M, Kwon P, Trogani N, Bhalla K, Remiszewski S. Molecular and cellular basis for the anti-proliferative effects of the HDAC inhibitor LAQ824. Novartis Found Symp. 2004;259:249-66; discussion 266-8, 285-8. PubMed PMID: 15171259.

19: Atadja P, Gao L, Kwon P, Trogani N, Walker H, Hsu M, Yeleswarapu L, Chandramouli N, Perez L, Versace R, Wu A, Sambucetti L, Lassota P, Cohen D, Bair K, Wood A, Remiszewski S. Selective growth inhibition of tumor cells by a novel histone deacetylase inhibitor, NVP-LAQ824. Cancer Res. 2004 Jan 15;64(2):689-95. PubMed PMID: 14744786.

20: Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H, Wang HG, Atadja P, Bhalla K. Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther. 2003 Oct;2(10):971-84. PubMed PMID: 14578462.

21: Remiszewski SW, Sambucetti LC, Bair KW, Bontempo J, Cesarz D, Chandramouli N, Chen R, Cheung M, Cornell-Kennon S, Dean K, Diamantidis G, France D, Green MA, Howell KL, Kashi R, Kwon P, Lassota P, Martin MS, Mou Y, Perez LB, Sharma S, Smith T, Sorensen E, Taplin F, Trogani N, Versace R, Walker H, Weltchek-Engler S, Wood A, Wu A, Atadja P. N-hydroxy-3-phenyl-2-propenamides as novel inhibitors of human histone deacetylase with in vivo antitumor activity: discovery of (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl ]-2-propenamide (NVP-LAQ824). J Med Chem. 2003 Oct 9;46(21):4609-24. PubMed PMID: 14521422.

22: Nimmanapalli R, Fuino L, Bali P, Gasparetto M, Glozak M, Tao J, Moscinski L, Smith C, Wu J, Jove R, Atadja P, Bhalla K. Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res. 2003 Aug 15;63(16):5126-35. PubMed PMID: 12941844.

23: Catley L, Weisberg E, Tai YT, Atadja P, Remiszewski S, Hideshima T, Mitsiades N, Shringarpure R, LeBlanc R, Chauhan D, Munshi NC, Schlossman R, Richardson P, Griffin J, Anderson KC. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood. 2003 Oct 1;102(7):2615-22. Epub 2003 Jun 19. PubMed PMID: 12816865.