Editorial [Hot Topic: Targeting Protein Kinases in Drug Discovery and Medicinal Chemistry (Guest Editor: Jeffrey Jie-Lou Liao)]

Human kinome contains 518 members. Over 150 protein kinases are associated with various diseases including cancer. Protein kinase drug discovery now is a hot area in the pharmaceutical industry. Currently, it is estimated that approximately 1/4-1/3 of drug discovery programs target protein kinases. However, identification of highly selective small-molecule inhibitors with suitable PK properties for a protein kinase target frequently presents a challenging problem in a kinase drug discovery program, mostly because of highly conserved nature of the catalytic domain in sequence and structure. Despite a significant number of disease-associated protein kinases, only a limited number of kinases have been successfully targeted by seven FDAapproved small-molecule drugs so far, highlighting the need for novel strategies and methods in the field. This issue reviews most recent advances in molecular targeting protein kinases in drug discovery and medicinal chemistry. The issue starts with the review of the major concerns and the rationalization of the serendipity in the history of protein kinase drug discovery. In this paper, a novel picture where the selectivity profile of a protein kinase inhibitor can be correlated with its resistant mutation profile is provided. This analysis could offer a potential for a future kinase program to optimize the profile of a lead compound with the ability to induce resistant mutation in the target, which is a major obstacle in kinase-targeted cancer therapy, in early-stage development. Halogen bonding has been known in organic chemistry since the 1950s. However, it seems not to be widely recognized by medicinal chemists although halogen bonding interaction has been used empirically in some drug discovery programs. Professor P. Shing Ho and his group re-discovered the significance of this type of interaction in protein-ligand systems guided by the first principle recently. In this issue, Andrea Regier Voth and P. Shing Ho investigate the role of halogen bonding in inhibitor recognition and binding by protein kinases. The overexpression of the serine/threonine kinase Akt in the PI3K/Akt pathway is implicated in a number of human cancers. Drs. Lindsley, Layton and their colleagues from Merck Research Laboratories describe recent advances in the development and biological evaluation of small-molecule inhibitors for this promising target. The RAS/RAF/MEK/ERK signaling pathway has been a major clinical focus in oncology research in recent years. Drs. Wang, Wilcoxen, Nomoto and Wu review recent advances of MEK inhibitors targeting this pathway. VEGFR-associated vascular angiogenesis plays a key role in many solid tumors. The review of Professor Bowen and Dr. Zhong discusses most recently developed VEGFR inhibitors. As targeting a highly specific inactive protein kinase conformation has become a major approach to design kinase inhibitors with a high degree of selectivity, binding a kinase target into multiple conformations is emerging as a key method to develop inhibitors with distinct but clinical useful profiles. Drs. Liao and Andrews present this structure-based strategy in detail in their article. Dr. Gill and his colleagues demonstrate in their paper that protein kinase small-molecule inhibitors have physicochemical property profiles distinguished from other types of marketed oral drugs. The articles in this issue contributed from six research groups cover important aspects of molecular targeting of protein kinases, providing the structure-based strategy, novel insight into molecular recognition of protein kinases and updates for the development of kinase inhibitors for important signal transduction pathways. It is my hope that these contributions will benefit R & D in the field. I would like to thank all authors who contribute to this issue and, in particular, Dr. Allen B. Reitz for inviting me to be Guest Editor of this issue.