Current Topics in Medicinal Chemistry - Volume 7, Issue 14, 2007

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.

This article reviews several important observations in the field of protein kinase drug discovery, exemplified mainly by targeting c-Abl for the treatment of CML. Structure-based strategy and insight are provided for the optimization of the selectivity and resistant mutation profiles of protein kinase inhibitors.

Halogen bonds are short-range molecular interactions that are analogous to classical hydrogen bonds, except that a polarized halogen replaces the hydrogen as the acid in the Lewis acid/base pair. Such interactions occur regularly in the structures of many ligand-protein complexes, but have only recently been recognized in biological systems as a distinct class with well-defined physical characteristics. In this review, we survey twelve single crystal structures of protein kinase complexes with halogenated ligands in order to characterize the role of halogen bonds in conferring specificity and affinity for halogenated inhibitors in this important class of enzymes. From this survey, we attempt to identify the properties of halogen bonds that can be generally applied to bottom-up strategies for designing inhibitors for this and other enzyme targets.

This article describes recent advances in the development and biological evaluation of small molecule inhibitors for the serine/threonine kinase Akt (PKB). Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the PI3K/Akt pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers. Akt is considered an attractive target for cancer therapy and inhibition of Akt alone or in combination with standard cancer chemotherapeutics has been postulated to reduce the apoptotic threshold and preferentially kill cancer cells. The development of specific and potent inhibitors will allow this hypothesis to be tested in animals. Recently, several series of small molecule, ATP-competitive inhibitors have been reported with a range of Akt potencies and selectivities. Phosphatidylinositol (PI) analogs have been reported to inhibit Akt, but these inhibitors may also have specificity problems with respect to other pleckstrin homology (PH) domain containing proteins and may have poor bioavailability. In addition, novel allosteric inhibitors have been reported which are PH domain dependent, exhibit selectivity for the individual Akt isozymes and inhibit the activity and the activation of Akt. Compounds within these classes Akt inhibitors have sufficient potency and specificity to test for tumor efficacy in animal models and recently reported preliminary experiments are reviewed.

The RAS/RAF/MEK/ERK signaling pathway has been a major clinical focus in oncology research in recent years. A clearer association of B-RAF mutations to cancers such as melanoma, papillary thyroid cancer and others has brought an increasing interest in chemotherapeutics that target this cellular signaling pathway. In this review, the authors summarize the current understanding of science and therapeutic use of the MEK inhibitors targeting the RAS/RAF/ MEK/ERK pathway. Clinical progresses of PD0325901 and AZD6244 are highlighted in addition to developments of new MEK inhibitors. Recently disclosed MEK inhibitors in two sub-divided classes, ATP noncompetitive and ATP competitive inhibitors are discussed.

Vascular angiogenesis has been shown to play a key role in many solid tumors. The vascular endothelial growth factor (VEGF) isoforms and their tyrosine kinase receptors (VEGFRs) have been under intense research for effective anticancer drug candidates. Epidermal growth factor (EGF) and its receptor (EGFR) provide another pathway critical in monitoring angiogenesis. VEGF exerts its effect through binding to tyrosine kinase receptors, mainly VEGFR-1 (Flt-1, the fms-like tyrosine kinase-1) and VEGFR-2 (Flk-1/KDR, fetal liver kinase-1). This paper reviews the progress, mechanism, and binding modes of recently approved kinase inhibitors, such as sunitinib (Sutent®), sorafenib (Nexavar®) and dasatinib (Sprycel®), as well as other inhibitors that are still under clinical development. Recent clinical treatments suggest that most inhibitors of VEGFR (and/or EGFR) exert their therapeutic effect through not only targeting the VEGFR (and/or EGFR) pathway, but also inhibiting other pathways, such as RAF/MEK/ERK pathway. A new pharmacophore model for second generation of type II tyrosine kinase inhibitors and recent advances in the combination of VEGFR tyrosine kinase inhibitors and other chemotherapeutics are also covered.

Multiple conformations of a protein kinase target offer an opportunity to design small-molecule inhibitors with distinct but clinically useful profiles. This article analyzes and classifies the binding pockets in the kinase catalytic cleft in different conformational states. Targeting kinase multiple conformations as an emerging strategy in the field is exemplified with important small-molecule agents in the clinic. The structure-based analysis in the paper provides a rationale for thwarting the development of drug-resistant mutations in antikinase therapy.

This manuscript describes a comparison of the physicochemical properties of marketed oral drugs with those of 45 structurally confirmed orally bioavailable anti-cancer protein kinase inhibitors currently in different phases of clinical development. It is evident from the data presented that these kinase inhibitors are on average larger (over 110Da), more lipophilic (over 1.5 log units) and more complex (approximately two more rotatable bonds) than those of marketed oral drugs. In contrast, hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) counts are not significantly different.

An Illicit Reduction. The passage of the Combat Methamphetamine Epidemic Act of 2005 and the declaration of November 30th, 2006 as “National Methamphetamine Awareness Day” by the US Drug Enforcement Administration represent a bit more public attention than usual for a Schedule II sympathomimetic amine approved in the US for the treatment of narcolepsy and attention deficit disorder. Even pseudoephedrine, a decongestant marketed as an ingredient in hundreds of over-the-counter medications and the chemical precursor of choice for the illicit production of methamphetamine, has found itself replaced in a number of cold medicine formulations with the less synthetically exploitable (and perhaps less efficacious) phenylephrine.1 A brief perusal of the Internet reveals numerous sites espousing practical modes of manufacture of methamphetamine from pseudoephedrine, most with the detail of an Organic Syntheses preparation complete with discussions of absolute vs. relative configuration. Commonly described routes include the “red, white, and blue protocol” (red phosphorus, white pseudoephedrine, and blue iodine) and the Birch reduction, wherein rechargeable batteries appear to be the preferred source of metallic lithium. This ease of synthesis and availability of starting materials had previously ensured illicit American-made methamphetamine could meet demand, but recent restrictions on pseudoephedrine have succeeded in severely damaging domestic production. The National Drug Threat Assessment of 2007 reports superlab seizures (labs capable of producing 10 lbs./batch) are down from 244 in 2001 to only 35 in 2005, yet the frequency of misuse (38.8% of state/local law enforcement report methamphetamine as the greatest drug threat) remains alarmingly high. Importation from Mexican labs has been steadily increasing, with seized Mexican methamphetamine rising from 2706 lbs. in 2003 to 4346 lbs. in 2005.2 With covert US production smarting and importation on the rise it seems legislative efforts to curb methamphetamine availability have changed the nature of the “war on meth” to parallel that of another stimulant, cocaine. REFERENCES [1] Hendeles, L., Hatton, R.C. J. Allergy Clin. Immunol. 2006, Vol 118(1), p. 279. [2] National Drug Threat Assessment 2007, compiled by the US Department of Justice. Available at www.usdoj.gov/ndic.