Thursday, June 11, 2015

Drugs in Clinical Pipeline: Quisinostat

Quisinostat [N-hydroxy-2-(4-((((1-methyl-1H-indol-3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide] is an orally bioavailable, second-generation, HDAC ( histone deacetylase) inhibitor based on hydroxamic acid. Quisinostat inhibits HDACs, which may result in the accumulation of highly acetylated histones, followed by the induction of chromatin remodeling; the selective transcription of tumor suppressor genes; the tumor suppressor protein-mediated inhibition of tumor cell division; and, finally, the induction of tumor cell apoptosis. It has the potential antineoplastic activity. Compared to some first generation HDAC inhibitors, JNJ-26481585 may induce superior HSP70 upregulation and bcl-2 downregulation.

Quisinostat is a novel second-generation HDAC inhibitor with highest potency for HDAC1 with IC50 of 0.11 nM in a cell-free assay. The compound exhibits greater than 30-fold selectivity against HDACs 3, 5, 8 and 9, with lowest potency for HDACs 6 and 7. It also displays broad spectrum antiproliferative activity in solid and hematologic cancer cell lines, such as all lung, breast, colon, prostate, brain, and ovarian tumor cell lines, with IC50 ranging from 3.1-246 nM, which is more potent than vorinostat, R306465, panobinostat, CRA-24781, or mocetinostat in various human cancer cell lines tested [1]. 

The activity of Quisinostat is as follows:

IC50 (HDAC1 cell-free assay) = 0.11 nM
IC50 (HDAC2 cell-free assay) = 0.33 nM
IC50 (HDAC11 cell-free assay) = 0.37 nM
IC50 (HDAC10 cell-free assay) = 0.46 nM
IC50 (HDAC4 cell-free assay) = 0.64 nM
IC50 (HDAC5 cell-free assay) = 3.69 nM
IC50 (HDAC8 cell-free assay) = 4.26 nM
IC50 (HDAC3 cell-free assay) = 4.86 nM
IC50 (HDAC9 cell-free assay) = 32.1 nM
IC50 (HDAC6 cell-free assay) = 76.8 nM
IC50 (HDAC7 cell-free assay) = 119 nM

Common Name: Quisinostat
Synonyms:  JNJ-26481585; JNJ26481585; JNJ 26481585
IUPAC Name: N-hydroxy-2-(4-((((1-methyl-1H-indol-3-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidine-5-carboxamide
CAS Number: 875320-29-9
Mechanism of Action: Second generation, HDAC Inhibitor
Indication: Lymphoma, T-cell, Cutaneous
Development Stage: Phase II
Company: Janssen Research and Development, LLC

HDACs are a class of enzymes that remove acetyl group (O=C-CH3) from an e-N-acetyl lysine amino acid on a histone. This allows the histone to wrap the DNA more tightly. It’s important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC proteins are also called lysine deacetylases (KDAC), to describe their function rather than their target, which also included non-histone proteins. Altered expression and mutations of genes that encode HDACs have been linked to tumor development since they both induce the aberrant transcription of key genes regulating important cellular functions such as cell proliferation, cell-cycle regulation and apoptosis. Thus, HDACs are among the most promising therapeutic targets for cancer treatment, and they have inspired researchers to study and develop HDAC inhibitors. HDACs (except class III) contain Zinc and are also known as Zn-dependent histone deacetylases.

In vivo pharmacodynamics analysis of potent pyrimidyl-hydroxamic acid analogues resulted in the identification of Quisinostat. Once daily oral administration of the compound induced continuous histone H3 acetylation. Quisinostat, was found to induce the HDAC1-suppressed p21waf1,cip1 promoter in vivo, and a continuous pharmacodynamics response (histone H3 acetylation) in tumor tissue. The compound completely inhibited the growth of Ras mutant pre-established HCT116 colon xenografts, 5-FU (5-fluorouracil) and Vorinostat displayed only modest activity under same settings. It was noted that, although Quisinostat strongly inhibited tumor growth in vivo of Ras mutant NSCLC xenografts, no efficacy in vivo was observed in Ras wild-type NCI-H1703 NSCLC xenografts. In human colon cancer cell lines, in vitro, Quisinostat induced potent apoptosis at 3 to 30 nM/L, both in APC wild-type (HCT116) and in APC mutant (HT-29) backgrounds [1].

Quisinostat also potently upregulated the HDAC1-suppressed expression of E-cadherin (at 30 nM conc.), which resulted in sensitization to epidermal growth factor receptor inhibitors in NSCLCs [2].

A recent study shows that Quisinostat promotes myeloma cell death at low nanomolar concentrations by resulting in Mcl-1 depletion and Hsp72 induction [3].

1. Arts, J.; et. al. JNJ-26481585, a novel “second-generation” oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin Cancer Res 200915(22), 6841-6851.
2. Witta, S. E.; et. al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res. 2006, 66(2), 944-950.
3. Stuhmer, T.; et al. Preclinical anti-myeloma activity of the novel HDAC-inhibitor JNJ-26481585. Br J Haematol 2010149(4), 529-536.
4. Tong, W. G.; et. al. Preclinical antileukemia activity of JNJ-26481585, a potent second-generation histone deacetylase inhibitor. Leuk Res 201034(2), 221-228.
5. Venugopal, B.; et. al. A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors. Clin Cancer Res 201319(15), 4262-4272.
6. Carol, H.; et. al. Initial testing (stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ-26481585), by the pediatric preclinical testing program. Pediatr. Blood Cancer 201461(2), 245-252.