Recent Advances in Thrombopoietic Small Molecules

Author(s): Ryuichi Sakai, Takanori Nakamura, Hisao Kamiya.

Journal Name:Current Bioactive Compounds

Volume 2 , Issue 4 , 2006

Abstract:

Proliferation and differentiation of stem cells are regulated by plural cytokines. One of those cytokines, thrombopoietin (TPO), a 332 amino acid protein, stimulates proliferation of hematopoietic stem cells, and differentiates them into megakaryocytic progenitor cells which in turn transform into megakaryocytes, direct precursors of platelets. Dysfunction in platelet production - thrombocytopenia, which can contribute to further bleeding complications and mortality, is often accompanied by cancer chemotherapy and/or radiation therapy. Since platelet transfusion is the only treatment for thrombocytopenia, drugs that possess TPO-like action, and that are administered orally, would be of great clinical benefit. Recently, a number of studies dealing with discovery and biological actions of non-peptide small molecule TPO mimics have been disclosed. These studies lead to a general understanding that small aromatic compounds can be true agonists for TPO receptors with full efficacy identical to that of TPO. Structure-activity relationship studies and pharmacological investigations with these molecules started to reveal pharmacophore and mechanisms of actions. However, exact mechanisms showing how the receptor is activated by small molecules are still to be investigated. Several different classes of molecules identified as c-Mpl agonists, including benzodiazepine, hydrazinonaphthalenes, substituted thiophenes, or thiazoles, may suggest plural pharmacophores and mechanisms underlying activation of the receptor. Recently a fungal product xanthocillin was discovered to have this activity, showing natural products can be an interesting source for the new structure. Further recruitment of diverse types of molecules with this activity will facilitate deeper insight into the mechanism of activation on a molecular basis. This review focuses on the chemical and biological aspects of small molecule TPO agonists described to date.

Keywords: Cell Proliferation, salicylaldehyde, naphthoimidazoles, pharmacophores, NIP-004, xanthocillins

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Article Details

VOLUME: 2
ISSUE: 4
Year: 2006
Page: [395 - 408]
Pages: 14
DOI: 10.2174/157340706778992537
Price: $58