Small Molecules against Metastatic Tumors: Concrete Perspectives and Shattered Dreams

Abstract

Metastasis is the main cause of anti-cancer therapy failure, leading to unfavorable prognosis for patients. The true challenge to increase cancer patient life expectancy by making cancer a chronic disease with periodic but manageable relapses relies on the development of efficient therapeutic strategies specifically directed against key targets in the metastatic process. Traditional chemotherapy with classical alkylating agents, microtubule inhibitors, and antimetabolites has demonstrated its limited efficacy against metastatic cells due to their capacity to select chemo-resistant cell populations that undergo epithelial-to-mesenchymal transition (EMT), thus promoting the colonization of distant sites that, in turn, sustain the initial metastatic process. This scenario has prompted efforts aimed at discovering a wide variety of small molecules and biologics as potential anti-metastatic drugs directed against more specific targets known to be involved in the various stages of metastasis. In this short review, we give an overview of the most recent advances related to important families of antimetastatic small molecules: intracellular tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, KRAS inhibitors, and integrin antagonists. Although the majority of these small molecules are not yet approved and not available in the drug market, any information related to their stage of development could represent a precious and valuable tool to identify new targets in the endless fight against metastasis.

Keywords: KRAS inhibitors; RGD; anticancer therapy; cancer; cyclin dependent kinase inhibitors; integrin antagonists; metastasis; small molecules; solid tumors; tyrosine kinase inhibitors.

Figure 1

Selected tyrosine kinase inhibitors employed in anticancer therapy.

Figure 2

Recently FDA and EMA approved CDK inhibitors and KRAS inhibitors.

Scheme 1

Examples of RGD-based integrin antagonists and their use in targeted drug delivery.

Figure 3

Selected integrin antagonists tested in clinical trials as anticancer agents.