Preclinical anti-arthritic study and pharmacokinetic properties of a potent histone deacetylase inhibitor MPT0G009

Abstract

The pathology of rheumatoid arthritis includes synoviocyte proliferation and inflammatory mediator expression, which may result from dysregulated epigenetic control by histone deacetylase (HDAC). Thus, HDAC inhibitors may be useful for treating inflammatory disease. This was a preclinical study of the HDAC inhibitor, MPT0G009. The IC50 values of MPT0G009 for HDAC1, 2, 3, 6 and 8 enzymatic activities were significantly lower than those for the currently marketed HDAC inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat). In addition, MPT0G009 markedly inhibited cytokine secretion and macrophage colony-stimulating factor/receptor activator of nuclear factor kappa B ligand-induced osteoclastogenesis by macrophages (50 ng/ml each). These MPT0G009 effects on cytokine secretion and osteoclast formation were reduced by the overexpression of HDAC 1 (class I HDAC) and 6 (class II HDAC) in cells, suggesting that these effects were due to the inhibition of its activity. In an in vivo rat model, oral administration of MPT0G009 (25 mg/kg) significantly inhibited paw swelling and bone destruction. Furthermore, compared with SAHA, MPT0G009 exhibited longer half-life (9.53 h for oral administration) and higher oral bioavailability (13%) in rats. These results established the preclinical anti-arthritic efficacy and pharmacokinetic parameters of MPT0G009, which may provide a new therapeutic approach for treating inflammatory arthritis.

Histone deacetylases (HDAC) in physiological and pathological bone remodelling

“…MPT0G009 is a non-selective HDACi that inhibits both class I (HDAC 1, 2, 3, 8) and class IIb (HDAC 6) HDACs (Table 1) [21]. Treatment with MPT0G009 at 25 mg/kg resulted in similar effects to that seen with vorinostat at 200 mg/kg.…”

“…The broad spectrum HDACi, MPT0G009, that inhibits multiple HDACs including HDAC 6 (IC 50 8 nM, Table 2), was shown to suppress osteoclast differentiation and activity in human and murine RAW264.7 cells, respectively [21]. Recent studies support the idea that inhibition of both class I (HDAC 1) and II (HDAC 6) HDACs may be necessary to suppress osteoclast differentiation and activity.…”

“…Vorinostat has been evaluated in rodent models of arthritis and anti-inflammatory activity was observed at doses of 50 mg/kg/day via subcutaneous injection [7] and 200 mg/kg/day via oral gavage [21]. However, these represent extremely high doses and raise concerns that long-term treatment of patients with chronic disease may reveal considerable unwanted off-target effects.…”

“…HDACi have also been shown to suppress inflammation and disease progression in a number of animal models of rheumatoid arthritis (RA) [7,[21][22][23]. Despite this, only one HDACi, Givinostat, has so far progressed to clinical trials for the treatment of juvenile arthritis [24].…”

“…The fact that HDACi are a new class of drugs that might help combat the ongoing bone damage associated with RA, has prompted a number of in vitro and in vivo RA related studies [7,[21][22][23][99][100][101]. The first study to assess effects of HDACi using an animal model of inflammatory arthritis was reported in 2003 [85].…”