Drugs in Clinical Pipeline: Pracinostat

Pracinostat [(E)-3-(2-butyl-1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide] is an orally bioavailable, small-molecule pan-HDAC (histone deacetylase inhibitor) based on hydroxamic acid. Pracinostat 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 [1]. It is potent in its activity, having K_i values of 16-48 nM [with the exception of HDAC6 (247 nM)], and it is also selective. In particular, it does not inhibit [3H]-dofetilide binding to the human Ether-à-go-go Related Gene potassium channel.

Pracinostat possess favourable metabolic, pharmacokinetic and pharmacological properties compared to other HDAC inhibitors [2].

Pracinostat has shown evidence of single-agent activity in multiple clinical trials, including advanced hematologic malignancies such as MDS, acute myeloid leukemia and myelofibrosis. Pracinostat has also demonstrated pre-clinical activity in hematologic disorders and solid tumors when used alone or in combination with a wide range of therapies in laboratory studies [3].

In March 2014, Pracinostat was approved for rare disease (orphan disease) acute myelocytic leukemia (AML) and for the treatment of T-cell lymphoma by the Food and Drug Administration. Acute myeloid leukemia (also known as acute myelogenous leukemia or acute nonlymphocytic leukemia (ANLL), is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults, and its incidence is expected to increase as the population ages.

The activity of Pracinostat is as follows:

IC₅₀ (HDAC1 enzyme assay) = 49 nM

IC₅₀ (HDAC2 enzyme assay) = 96 nM

IC₅₀ (HDAC3 enzyme assay) = 43 nM

IC₅₀ (HDAC8 enzyme assay) = 140 nM

IC₅₀ (HDAC4 enzyme assay) = 56 nM

IC₅₀ (HDAC5 enzyme assay) = 47 nM

IC₅₀ (HDAC7 enzyme assay) = 137 nM

IC₅₀ (HDAC9 enzyme assay) = 70 nM

IC₅₀ (HDAC10 enzyme assay) = 40 nM

IC₅₀ (HDAC11 enzyme assay) = 93 nM

Common Name: Pracinostat

Synonyms:  SB939; SB 939; SC-939

IUPAC Name: (E)-3-(2-butyl-1-(2-(diethylamino)ethyl)-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide

CAS Number: 929016-96-6

SMILES: CCCCC1=NC2=C(N1CCN(CC)CC)C=CC(=C2)/C=C/C(=O)NO

Mechanism of Action: HDAC Inhibitor; pan-HDAC Inhibitor

Indication: Elderly Acute Myeloid Leukemia (AML)

Development Stage: Phase III

Company: MEI Pharma Inc (MEIP)

HDAC 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.

Pracinostat has a 100-fold greater selectivity for HDACs than for Zn-binding non-HDAC enzymes, receptors and ion channels. It selectively inhibits HDAC class I, II, IV without class III and HDAC6 in class IV [2]. It shows significant antiproliferative activity against a wide variety of tumor cell lines, especially Leukemia cells and cutaneous T-cell Lymphoma cells with IC₅₀ values ranging from 50 nM (H9 cells) to 170 nM (HEL92.1.7 cells) [2].

In preclinical in vivo studies, orally administered SB939 demonstrated dose-dependent antitumor activity against a variety of experimental solid tumor models and was found to selectively accumulate in tumor tissue, as evidenced by concentrations that were 10-fold higher than those in plasma, liver, kidney, and lung tissue. Repeated oral dosing studies showed it had a good safety profile in animals. The favorable pharmacological properties of SB939 including high aqueous solubility, tissue permeability, and no major interaction with cytochrome P-450 isoenzymes, which indicate best-in-class potential [4].

In a Phase I study to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SB939, dose-escalating cohorts of three to six patients (36 patients) received SB939 orally thrice weekly for 3 weeks in a 4-week cycle. Acetylated histone H3 (acH3) was measured in peripheral blood mononuclear cells (PBMCs). The MTD of SB939 was 80 mg/day. The mean elimination half-life and oral clearance of SB939 were 7.2 ± 0.6 h and 53.0 ± 8.5 l/h, respectively, with no substantial accumulation on day 15. An increase in acH3 was observed at hour 3 and correlated with dose and Peak plasma concentration (Cmax). Stable disease was seen in several tumor types treated at = 40 mg. HDAC inhibition was consistently observed at 60 mg, the recommended dose. Dose-limiting toxic effects were fatigue, hypokalemia, troponin T elevation, and QTc prolongation [4].

Pracinostat failed phase 2 trials when tested in combination with another cancer drug Azacitidine (hypomethylation agent) for Myelodysplastic syndrome (MDS) [5]. Data from the phase 2 trial illustrated that the combination treatment was no more effective in inducing complete responses than Azacitidine alone [6].

References:

1.    Novotny-Diermayr, V.; et. al. The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML. Blood Cancer J 2012, 2(5), e69.

2.    Novotny-Diermayr, V. et. al. SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal Cancer. Mol Cancer Ther 2010, 9(3), 642-652.

3. Sangthongpitag, K.; et. al. SB939: A Potent and Orally Active HDAC Inhibitor for the Treatment of Hematological Malignancies. Blood 2007, 110.

4.    Goh, B. B.; et. al. Phase I and pharmacodynamic study of an orally administered novel inhibitor of histone deacetylases, SB939, in patients with refractory solid malignancies. Ann Oncol 2011, 22(11), 2516-2522.

5.    Montalban-Bravo, G.; et. al. Novel drugs for older patients with acute myeloid leukemia. Leukemia 2015, 29(4), 760-769.

6. Bose, P.; et. al. Orphan drug designation for pracinostat, volasertib and alvocidib in AML. Leuk Res 2014, 38(8), 862-865.