Vitamin K was discovered in 1929 as an essential factor required for normal hemostasis, but it was not until 1974 that it was found out that vitamin K functions as a cofactor for the enzyme gammaglutamyl carboxylase in the synthesis of an unusual amino acid called gammacarboxy glutamate (Gla). Vitamin K is a group name for a number of related compounds which share a naphthoquinone nucleusincluding vitamin K1, K2 and K3. Gla is important for the biological functioning of a number of proteins involved in bone structure and hence, as described in a recent DiscoveryDossier, vitamin K represents an excellent target for the development of new treatments of osteoporosis. In contrast to vitamin K1 and independent of gammaglutamyl carboxylase activity, vitamin K2 has been suggested to modulate the prenylation of growth factors required for osteoclast activation thereby inhibiting osteoclastogenesis. Hence vitamin K2 mimics may be of particular use in the treatment of osteoporosis.

In addition to representing a treatment for osteoporosis, K vitamins, also inhibit cell growth both in vitro and in vivo, with vitamin K3 being more potent than vitamin K1 and K2. In 1995, University of Pittsburgh researchers synthesized a thioalkyl analog of vitamin K (2-(2-mercaptoethanol)-3-methyl-1, 4-naphthoquinone; Cpd 5) which was able to interact with cellular thiols or thiol-dependent proteins. This interaction was via position 3 of its quinoid nuclei.

In particular, Cpd 5 has been suggested to arylate catalytic cysteine(s) found in protein PTPases thereby inactivating them. The Cdc25 phosphatase family is one family of protein tyrosine phosphatases that has an essential role in cell cycle progression, representatives of which activate Cdks. Treatment of cells with Cpd 5 has been shown to block Cdc25C. This prevents the activation of the mitotic kinase Cdc2/cyclin B, which is required for entry into mitosis. Likewise Cpd 5 also inhibits Cdc25A which is responsible for the activation of Cdk 4, an important regulator for G(1) progression. In addition to activating the Cdks directly, Cdc25 is also able to activate ERK kinase and the ability of Cpd 5 to cause a sustained increase in the phosphorylation of ERK/MAP kinase further reduces the activity of Cdks. This confers potent growth inhibitory activity to Cpd 25 and its analogues in at least 13 different human cancer cell lines.

Most recently the University of Pittsburgh Group in collaboration with researchers at the Academia Sinica in Taiwan and at the CNRS in France published a thorough evaluation of the effects of Cpd 5 on cell cycle proteins. This study demonstrated that Cpd 5 decreased the levels of cyclin D1, Cdk4, p16, p21 and cyclin B1. The main effects of Cpd 5 were on G1 and S phase proteins, especially Cdk4 and Cdc25A contrasting with Vitamin K3. Computer docking studies of Cpd 5 and Vitamin K3 to Cdc25A phosphatase showed three binding sites. In the best conformation, Cpd 5 was found to be closer to the enzyme active site than Vitamin K3. These findings confirm that Cpd 5 represents a new class of anticancer agent, being a protein tyrosine phosphatase antagonist that binds to Cdc25A with suppression of its activity. Tumors expressing high levels of oncogenic Cdc25A phosphatase may thus be susceptible to the growth inhibitory activities of this class of compound and the further development of this therapeutic candidate and related compounds is eagerly awaited.

Entry date Monday, May 19, 2003

Adapted from Markovits et al, Life Sci 2003 May 2;72(24):2769-84 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

For a full list of publications relating to Cpd 5 please click here.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk