Thursday, September 3, 2015

Drugs in Clinical Pipeline: MC1568

MC1568 [(E)-3-(5-((E)-3-(3-fluorophenyl)-3-oxoprop-1-en-1-yl)-1-methyl-1H-pyrrol-2-yl)-N-hydroxyacrylamide], one of the only known selective inhibitors of class IIa histone deacetylase (HDAC) enzymes to be documented in the literature till date. It was identified from a series of novel (aryloxopropenyl)-pyrrolyl hydroxyamides which are structurally related to aroyl-pyrrolyl-hydroxy-amides (APHAs) and were highly selective against the class II (class IIa) histone deacetylase homologue HD1-A. The compound has also been the starting point for a number of structure-activity relationship and molecular modelling studies.

MC1568 was tested against maize HD1-B and HD1-A two mammalian class I and class II (IIa) HDAC homologues. It inhibited HD1-B and HD1-A with IC50 value 38.8 ± 1.16 and 0.22 ± 0.01 uM, respectively. The selectivity index was 176.4 in favour of class IIa. Moreover, its maize HD2 50% inhibitory activity (IC50) was found to be 22.0 ± 1.32 uM.

Being the most selective compound in the maize HD1-B/ HD1-A system, MC1568 was evaluated against human HDAC1 and HDAC4 in comparison with SAHA as reference drug. Human breast cancer ZR-75.1 cell lysates were immunoprecipitated with antibodies against HDAC1 and HDAC4, and inhibitory assays were performed on such immunoprecipitates (IPs) with MC1568 (5 µM) and SAHA (5 µM). Data reported clearly show that MC1568 lacked any inhibitory activity against human HDAC1 (% inhibition of 5 uM = 0%) but was effective in inhibiting human HDAC4 enzyme (% inhibition of 5 uM = 54.9 %) [1].

The activity of MC1568 is as follows:

% Inhibition of HDAC1 @ 5 uM = 0 %

% Inhibition of HDAC4 @ 5 uM = 54.9 %

Common Name: MC1568
Synonyms: MC1568; MC 1568; MC-1568
IUPAC Name: (E)-3-(5-((E)-3-(3-fluorophenyl)-3-oxoprop-1-en-1-yl)-1-methyl-1H-pyrrol-2-yl)-N-hydroxyacrylamide
CAS Number: 852475-26-4
Mechanism of Action: HDAC Inhibitor; Histone Deacetylase Inhibitor; HDAC4 Inhibitor
Indication: Various Cancers
Development Stage: Investigational
Company: Italian University

1. Mai, M.; et. al. Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxyamides. J Med Chem 2005, 48(9), 3344-3353.