The retinoids play a key role in differentiation, proliferation and apoptosis. Since each of these processes play a part in tumor progression almost 20 naturally occurring and synthetic analogs of retinoic acid are now either in development or on the market as anti-cancer treatments. Although efficacy has been demonstrated in acute promyelocytic leukemia and various skin cancers, the extension of therapeutic benefit to other cancers has been limited. In our recent dossier “Retinoids: An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development” we set out to offer a full and up to date insight into the complexities of the retinoids and strategies for improving their therapeutic efficacy.

Most retinoids developed to date target the nuclear retinoid receptors however in our previous edition of TherapeuticAdvances we highlighted work showing that synthetic retinoids are able to stimulate apoptosis without binding to retinoid receptors. This may lead to the development of molecules with multiple mechanisms of action and with possible improvements in efficacy. Studies by Javi Piedrafita and colleagues at Sidney Kimmel Cancer Center, San Diego, have revealed that these retinoids activate the intrinsic apoptosis pathway and associated down-stream caspases.

NF-kappaB is overexpressed or constitutively activated in many cancer cells, where it induces the expression of antiapoptotic genes correlating with resistance to anticancer therapies. In particular NF-kappaB induces the expression of IAP-1, IAP-2 and XIAP, three endogenous inhibitors of apoptosis that represent highly promising targets for oncology therapeutics (click here for our recent DiscoveryDossier on this subject). Small molecules that inhibit the NF-kappaB signaling pathway could therefore be used to induce apoptosis in NF-kappaB-overexpressing tumors and potentially serve as anticancer agents. This concept is further supported by data showing that NF-kappaB also plays a key role in angiogenesis and cellular proliferation.

Activation of NF-kappaB normally requires the phosphorylation and subsequent degradation of I-kappaB by I-kappaB kinase (IKK). Inhibitors of IKK therefore represent a therapeutic target. Of interest LeadDiscovery has recently featured the “Kinase Enterprise library”. This is a targeted library of candidate kinase inhibitors that is available for in house screening. Alternatively, options are available through which LeadDiscovery’s partner ChemOvation can dock this library into the active site of IKK using their suite of computational tools (Click here for further information on this library). Molecules with a similar structure to the retinoid antagonist MX781 may be of particular interest since Javi Piedrafita’s group has recently shown that this compound is able specifically and reversibly inhibit both IKKalpha and IKKbeta. This was paralleled by a complete inhibition of tumor necrosis factor alpha-mediated binding of NF-kappaB to DNA and correlated with reduced cell proliferation, reduced expression of IAP-2 and increased apoptosis. This pro-apoptotic activity was dependent on caspase activity but independent of the retinoid receptors.

These data have a number of important implications. Firstly, they offer proof of concept to support the development of IKK inhibitors as treatments of cancer. Secondly, molecular design based on the structure of MX781 may lead to the development of IKK inhibitors whose therapeutic activity is enhanced by addition retinoid receptor mediated activity. Finally, the kinase enterprise library could be screened in silico for molecules based on the structure of these retinoids in order to fast track the development of IKK inhibitors.

Entry date Monday, May 19, 2003

Adapted from Bayon et al, Mol Cell Biol 2003 Feb;23(3):1061-74 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

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