The 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway for isoprenoid biosynthesis has come under increased scrutiny as a target for novel antimalarial, antibacterial and herbicidal agents. 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a key enzyme of the pathway that catalyzes the rearrangement and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of 1-deoxy-D-xylulose 5-phosphate (DXP) to MEP. The unique properties of DXR make it a remarkable and rational target for drug design. First, it is a vital enzyme for synthesis of isoprenoids in algae, plants, several eubacteria including the pathogenic bacteria like Bacillus anthracis, Helicobacter pylori, Yersinia pestis, Mycobacterium tuberculosis and the malarial parasite, Plasmodium falciparum. Second, there are no functional equivalents to DXR in humans, making it an attractive target for therapeutic intervention. Third, DXR appears to be a valid target and the results from fosmidomycin (1), the only available DXR inhibitor under clinical trials, suggests synergistic effects with the lincosamide antibiotics, lincomycin and clindamycin. Despite drug design efforts in this area, no successful drug specifically designed to inhibit DXR has emerged yet. This review summarizes the recent and promising developments with respect to the current knowledge of the MEP pathway with emphasis on the understanding of the structure and the catalytic mechanism of the DXR enzyme and the global quest for therapeutically useful inhibitors of DXR.

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.

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.