Drugs in Clinical Pipeline: Tefinostat

Tefinostat [Cyclopentyl (S)-2-cyclohexyl-2-((4-(8-(hydroxyamino)-8-oxooctanamido) benzyl) amino)acetate] is a novel monocyte/macrophage-targeted histone deacetylase inhibitor (HDACi) that is cleaved to an active acid, CHR-2847, by an intracellular esterase (human carboxylesterase-1, hCE-1), found only in cells of monocytoid lineage and hepatocytes. 

Tefinostat and its acid CHR-2845 had similar 50% inhibitory concentrations (IC₅₀) when tested against the HDAC activity of HeLa cell nuclear extracts that contain multiple HDAC isoforms (113 nM for Tefinostat, 160 nM for CHR-2847, respectively).

CHR-2847, being a charged molecule, cannot readily leave cells and, hence, selectively accumulates and is active within hCE1- expressing cells, resulting in a 20- to 100-fold increase in the anti-proliferative potency of Tefinostat for monocytic, over non-monocytic, tumour cells. The Esterase Sensitive Motif (ESM) technology used to design Tefinostat is widely applicable and an increase in potency against monocytic tumour cell lines has been demonstrated with a variety of targets [1, 2].

Tefinostat is a much better substrate for hCE1 than for the related, and ubiquitously expressed, hCE2, as evidenced by the rate of production of CHR-2847 when hydrolysed by the two enzymes: thus hCE1 produces CHR-2847 at 4400 pg/ml/ min whereas hCE2 hydrolyses tefinostat much more slowly with a rate less than 200 pg/ml/min.                                

The activity of Tefinostat is as follows:

IC₅₀ (HDAC HeLa cell nuclear extract assay) = 113 nM

Common Name: Tefinostat

Synonyms: CHR-2845; CHR 2845; CHR2845

IUPAC Name: Cyclopentyl (S)-2-cyclohexyl-2-((4-(8-(hydroxyamino)-8-oxooctanamido) benzyl)amino)acetate

CAS Number: 914605-76-8

Mechanism of Action: HDAC Inhibitor; Histone Deacetylase Inhibitor

Indication: Various Cancers

Development Stage: Phase I/II

Company: Chroma Therapeutics

Phase I Study  [3]

In a first-in-human, standard 3 + 3 dose escalating trial of oral, once daily Tefinostat was conducted to determine the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tefinostat in relapsed/refractory haematological diseases. 

Eighteen patients were enrolled at doses of 20-640 mg. Plasma concentrations of Tefinostat exceeded those demonstrated to give in vitro anti-proliferative activity. Flow cytometric pharmacodynamic assays demonstrated monocyte-targeted increases in protein acetylation, without corresponding changes in lymphocytes. 

Dose-limiting toxicities (DLTs) were not observed and dose escalation was halted at 640 mg without identification of the maximum tolerated dose (MTD). Drug-related toxicities were largely Common Toxicity Criteria for Adverse Events grade 1/2 and included nausea, anorexia, fatigue, constipation, rash and increased blood creatinine. 

a: A patient with chronic monomyelocytic leukaemia achieved a bone marrow response, with no change in peripheral monocytes. 

b: An acute myeloid leukaemia type M2 patient showed a more than 50% decrease in bone marrow blasts and clearance of peripheral blasts. 

In conclusion, Tefinostat produces monocyte-targeted HDACi activity and is well tolerated, without the DLTs, e.g. fatigue, diarrhoea, thrombocytopenia, commonly seen with non-targeted HDACi. The early signs of efficacy and absence of significant toxicity warrant further evaluation of Tefinostat in larger studies.

References:

1. Ossenkoppele, G. J.; et. al. A phase I first-in-human study with tefinostat-a monocyte/macrophage targeted histone deacetylase inhibitor-in patients with advanced haematological malignancies. Br J Haematol 2013, 162(2), 191-201.

2. Needham, L.A.; et. al.  Drug targeting to monocytes and macrophages using esterase-sensitive chemical motifs. J Pharmacol Exp Ther 2011, 339, 132-142. 
3. Ossenkoppele, G. J.; et. al. A phase I first-in-human study with tefinostat - a monocyte/macrophage targeted histone deacetylase inhibitor-in patients with advanced haematological malignancies. Br J Haematol 2013, 162(2), 191-201.
4. ClinicalTrials.gov Safety and Tolerability of CHR-2845 to Treat Haematological Diseases or Lymphoid Malignancies (CHR-2845-001). NCT00820508 (retrieved 28-09-2015)