Receptor tyrosine kinases (RTK) are transmembrane receptors that regulate signal transduction in cells. As a member of the TAM (Tyro-3, Axl, Mer) RTK subfamily, Axl regulates key processes such as cell growth, migration, aggregation, and apoptosis through several pathways. Its overexpression/overactivation has been underlined in several conditions, especially cancers, and in both chemotherapy and targeted therapy sensitivity loss. In this review, we propose to highlight the therapeutic implication of Axl, starting with the pathways it regulates, validating its interest as a therapeutic target, and defining the tools available to develop strategies for its inhibition. We especially focus on small molecule inhibitors, their structure, inhibition profile, and development stages. Mol Cancer Ther; 13(9); 2141-8. Ó2014 AACR.

The c-Jun N-terminal kinase (JNK) family, with its three members JNK1, JNK2, and JNK3, is a subfamily of mitogen-activated protein kinases. Involved in many aspects of cellular processes, JNK has been also associated with pathological states such as neurodegenerative diseases, inflammation, and cancers. In oncology, each isoform plays a distinct role depending on the context of the targeted tissue/organ, the tumor stage, and, most likely, the signaling pathway activated upstream. Consequently, the current challenge in finding new successful anti-JNK therapies is to design isoform-selective inhibitors of the JNKs. In this review, a particular focus is given to the JNK inhibitors that have been developed thus far when examining 3D structures of various JNK-inhibitor complexes. Using current data regarding structure-activity relationships and medicinal chemistry approaches, our objective is to provide a better understanding of the design and development of selective JNK inhibitors in the present and future.

Approximately 30 therapeutic monoclonal antibodies have already been approved for cancers and inflammatory diseases, and monoclonal antibodies continue to be one of the fastest growing classes of therapeutic molecules. Because aberrant signaling by receptor tyrosine kinases (RTKs) is a commonly observed factor in cancer, most of the subclasses of RTKs are being extensively studied as potential targets for treating malignancies. The first two RTKs that have been targeted by antibody therapy, with five currently marketed antibodies, are the growth factor receptors EGFR and HER2. However, due to systemic side effects, refractory patients and the development of drug resistance, these treatments are being challenged by emerging therapeutics. This review examines current monoclonal antibody therapies against RTKs. After an analysis of agents that have already been approved, we present an analysis of antibodies in clinical development that target RTKs. Finally, we highlight promising RTKs that are emerging as new oncological targets for antibody-based therapy.

Efforts were made to improve a series of potent dual ABL/SRC inhibitors based on a 7-azaindole core with the aim of developing compounds that demonstrate a wider activity on selected oncogenic kinases. Multi-targeted kinase inhibitors (MTKIs) were then derived, focusing on kinases involved in both angiogenesis and tumorigenesis processes. Antiproliferative activity studies using different cellular models led to the discovery of a lead candidate (6z) that combined both antiangiogenic and antitumoral effects. The activity of 6z was assessed against a panel of kinases and cell lines including solid cancers and leukemia cell models to explore its potential therapeutic applications. With its potency and selectivity for oncogenic kinases, 6z was revealed to be a focused MTKI that should have a bright future in fighting a wide range of cancers.

The tyrosine kinase epidermal growth factor receptor (EGFR) has emerged in recent years as a key and validated target of targeted therapies for solid tumors. It plays a central role in oncology since it is involved in many steps of tumor progression such as proliferation, angiogenesis, invasiveness, decreased apoptosis, and loss of differentiation. Recent advances in targeted therapies have demonstrated that tyrosine kinase inhibitors (TKIs), have provided a marked benefit to subsets of patients whose tumors harbor specific genetic abnormalities. However, resistance phenomenon appears rapidly and patients with EGFR mutations acquire resistance to TKI inhibitors decreasing therefore the median time to disease progression to few months. Several strategies were envisioned to overcome this resistance, such as dual-target inhibitors, multitarget and combined therapy. This review summarizes recent advances in TKIs development with special focus on rational strategies for the design of potent EGFR inhibitors including molecular modeling studies based on crystallographic data. Such advances open the way for new research possibilities in modern medicinal chemistry combined to structure-based drug design.