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The SARfaris: GPCR, Kinase, ADME

Sunday, 4 November 2012

New Drug Approvals 2012 - Pt. XXIII - Omacetaxine mepesuccinate (SYNRIBOTM)

ATC code: L01XX40
Wikipedia: Omacetaxine_mepesuccinate

On October 22nd 2012 the FDA approved omacetaxine mepesuccinate (research code: CGX-635, trivial name: Homoharringtonine, trademark: SynriboTM) for the treatment of chronic or accelerated phase chronic myeloid leukaemia (CML) in adults with resistance to two or more tyrosine kinase inhibitors. Omacetaxine is an old drug identified 35 years ago and known to have activity in CML, but its clinical development was previously halted due to the discovery of BCL-ABL and other targeted kinase inhibitors Pubmed: 21294709. The rapid development of tyrosine kinase inhibitor resistant tumors has led to the need for agents that can act in these treatment-derived drug-resistant patients. Omacetaxine mepesuccinate has been approved based on observed major cytogenetic response rather than on improvement in disease-related symptoms or increased survival.

Omacetaxine mepesuccinate/homoharringtonine is a cephalotaxine ester of prepared by a semi-synthetic process from cephalotaxine, an extract from the leaves of Cephalotaxus sp found in Southern China. Its molecular formula is C29H39NO9, with an IUPAC name of 4-methyl (2R)-hydroxyl-2-(4-hydroxyl-4-methylpentyl) butanedioate, its molecular weight is 545.6 Da. It is absorbed following subcutaneous administration, and maximum plasma (Tmax) concentrations are achieved after ~30 minutes. The volume of distribution (Vd) is variable at 141 +/- 93.4 L following subcutaneous administration of 1.25 mg/m2 twice daily for 11 days.

The mechanistic target of omacetaxine mepesuccinate is not fully known, however its action includes inhibition of protein synthesis. It was found to bind to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit in archaeabacteria and is understood to prevent the correct positioning of amino acid side chains of incoming aminoacyl-tRNAs, thus inhibiting the elongation step of peptide synthesis. 

It was shown in vitro to reduce the protein levels of a number of oncogenic proteins including BCR-ABL and MCL1. Because it does not bind BRC-ABL directly, it is active both in wild-type and resistant tumours harbouring the ABL drug resistance mutant: T351I as seen in mouse models.

Prescribing information is here

SynriboTM is marketed by IVAX pharmaceuticals

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