Although hundreds of small-molecule kinase inhibitors have been investigated in the past decade, the number of agents obtaining marketing approval is comparatively low. Several factors might be responsible for this, including lack of selectivity and off-target adverse effects. In our first Review this month, Force and Kolaja discuss some of the mechanisms underlying the toxicity of small-molecule kinase inhibitors, focusing on adverse effects on the heart, and assess the ability of various preclinical safety models and strategies to predict the clinical cardiotoxicity of these agents. Dysregulated protein kinase activity commonly occurs in human tumour development, and in their Review, Quintás-Cardama and colleagues discuss the therapeutic significance of Janus kinases (JAKs) — particularly JAK2, which is mutated in the majority of myeloproliferative neoplasias (MPNs). Small-molecule JAK inhibitors currently under investigation to treat MPNs, rheumatological disorders, transplant rejection and other malignancies are reviewed. Another anticancer approach is the use of monoclonal antibodies targeted to antigens expressed on tumour cells. The Fc region of such antibodies mediates their effector functions, and has important roles in both their efficacy and safety. In this month's Perspective, Jiang and colleagues discuss these effector functions and present strategies to assess and control them for various classes of monoclonal antibodies. One monoclonal antibody, denosumab, recently received approval by the US FDA for the treatment of skeletal-related events in patients with solid tumours and bone metastases, in addition to its original indication of postmenopausal osteoporosis. In our final Review, Rosen and colleagues discuss the mechanisms of osteoporosis development and review emerging therapeutic strategies, particularly those aimed at promoting bone formation, rather than just preventing bone loss.
