Thalidomide analogues as anticancer drugs

Abstract

The evolution of thalidomide as an effective treatment in several neoplasms has led to the search for compounds with increased antiangiogenic and anti-tumor effects, but decreased side-effects. The development of thalidomide analogues which retain the immunomodulatory effects of the parent compound, while minimizing the adverse reactions, brought about a class of agents termed the Immunomodulatory drugs (IMiDs). The IMiDs have undergone significant advances in recent years as evidenced by the recent FDA-approvals of one of the lead compounds, CC-5013 (lenalidomide), for 5q-myelodysplasia and for multiple myeloma (MM). Actimid (CC-4047), another IMiD lead compound, has also undergone clinical testing in MM. Apart from hematologic malignancies, these drugs are actively under investigation in solid tumor malignancies including prostate cancer, melanoma, and gliomas, in which potent activity has been demonstrated. The preclinical and clinical data relating to these analogues, as well as ENMD-0995, are reviewed herein. Encouraging results with these thalidomide analogues brought forth synthesis and screening of additional novel thalidomide analogues in the N-substituted and tetrafluorinated classes, including CPS11 and CPS49. This review also discusses the patents and preclinical findings for these agents.

Fig. (1). Chemical structure of thalidomide, lenalidomide, and CC-4047

Fig (2). Mechanism of anti-angiogenic and immunomodulatory actions of IMiDs

Mechanisms of anti-angiogenic and immunomodulatory functions of IMiDs. Immunomodulatory drugs (IMiDs), like thalidomide metabolites upon oxidation, inhibits interleukin 1 β or TNF-alpha – induced activation of IκK, which prevents dissociation of IκBα from NFκB , precluding its nuclear translocation and induction of genes that function in metastasis, angiogenesis, cellular proliferation, inflammation, and protection from apoptosis. IMiDs and thalidomide metabolites also function in T cell activation as its T cell costimulatory function, enhancing T cell proliferation. The activated T cells release interleukin-2 (IL-2) and interferon-gamma (IFN-γ), which activate the Natural Killer cells (NK cells)

Fig. (3). The analogues CPS11, CPS45 and CPS49