Current Topics in Medicinal Chemistry - Volume 2, Issue 9, 2002

The worldwide population afflicted with diabetes is growing at an epidemic rate. There are almost five times the number of people suffering from this disease today as compared to 10 years ago and the worldwide diabetic population is expected to exceed 300 million by the year 2028. This trend appears to be driven by the world's adoption of a “western lifestyle” comprising a combination of unhealthy dietary habits and a sedentary daily routine. Today, diabetes is the sixth leading cause of death in the United States and the death rates associated with diabetes have increased by 30% over the last decade. While medications are available to reduce blood glucose, approximately one third of the patients on oral medications will eventually fail to respond and require insulin injections. Consequently, there is a tremendous medical need for improved medications to manage this disease that demonstrate superior efficacy. Emerging knowledge regarding the underlying mechanisms that impair glucose-stimulated insulin secretion and the action of insulin on its target tissues has grown tremendously over the last two decades. During that same period of time, an understanding of the important role that phosphorylation state plays in signal transduction has drawn attention to several kinases as attractive approaches for the treatment of diabetes. Recent advances include the discovery of a “small molecule” allosteric binding site on the insulin receptor, inhibitors of glycogen synthase kinase-3 (GSK-3) which improve insulin sensitivity in diabetic animal models and inhibitors of protein kinase C-β that are presently being evaluated in clinical trials for diabetic retinopathy. This review will detail these recent discoveries and highlight emerging biological targets that hold potential to normalize blood glucose and prevent the progression of diabetes related complications.

Over the past decade, protein kinases have emerged as a group of molecular targets with the potential to be “cancer-specific”, allowing the selective targeting of cancer cells versus normal cells. These selective anticancer drugs would eliminate the cytotoxic side effects that are associated with conventional cancer chemotherapy. This article will focus on two emerging and less-explored protein serine / threonine kinase targets: PKB / Akt and checkpoint kinase 1 (Chk1). Protein kinase B / Akts are a group of serine / threonine kinases that are overexpressed in a variety of human tumors. An Akt inhibitor would target the imbalance of pro-versus anti-apoptosis regulation in cancerous as compared to healthy cells. Thus, a greater therapeutic window than conventional cytotoxic chemotherapy is expected. Cell-cycle checkpoints have become attractive targets since some of them, such as the G1 / S checkpoint, are defective in most tumor cells. Inhibition of one or more of the remaining checkpoint(s) could make cancerous cells more sensitive than healthy cells toward DNA damaging agents or radiation therapy. Among the checkpoint kinases, Chk1 appears to be an attractive molecular target. Chk1 blocks the activation of the Cdc2-cyclin B kinase complex, and hence entry into mitosis, by disrupting the translocation of the phosphatase Cdc25C from the cyotoplasm to the nucleus. A limited number of small molecule inhibitors in this emerging field and their mode of action will be reviewed.

The Kinase insert Domain containing Receptor (KDR), alternatively referred to as VEGFR-2, is a receptor for Vascular Endothelial Growth Factors (VEGFs) and functions as a key regulator of angiogenesis, the process by which new capillaries are created from preexisting blood vessels. The induction of angiogenesis, or the “angiogenic switch,” is a critical step in tumor progression, and inhibitors of KDR have been demonstrated both to induce tumor regression and reduce metastatic potential in preclinical models. In the last few years, medicinal chemists have expanded the kinase selectivity profile of known inhibitor classes to include KDR, and also identified novel classes of KDR inhibitors. This review presents structure activity relationships (SAR) of small molecule inhibitors of KDR, with an emphasis on the pharmacophore elements of the scaffolds employed. Binding hypotheses based on X-ray crystallographic analyses will also be described. Additionally, the efficacy of representative compounds in in vitro and in vivo models of tumor progression and angiogenesis are discussed.

This review covers literature describing research progress in erbB family tyrosine kinase inhibition over the last year. Excellent recent reviews are available, thus we have focussed on current developments of leading small molecule drug candidates as well as their erbB family inhibition profile. The most advanced erbB family tyrosine kinase (TK) inhibitors are demonstrating promising anti-cancer activity in clinical trials and are discussed. Several inhibition strategies are emerging: EGFR TK selective, irreversible TK inhibition and dual EGFR / erbB2 TK inhibitors. While small structural differences are seen in the leading compounds, the variations in their inhibition profiles and compound properties suggest that biological systems judge structural diversity differently. The readers' attention is drawn to common issues of selectivity and potency generally encountered with kinase inhibitors.

The p38 MAP kinase is thought to be involved in a variety of inflammatory and immunological disorders such as rheumatoid arthritis. The pyridinylimidazole class of compounds was the first to potently inhibit this kinase. Since the original reports of their efficacy, they have become the most widely studied series of inhibitors of this kinase. This framework has served as a starting point for further synthetic work and several compounds have entered clinical trials. These compounds have also been utilized to elucidate the role of p38 kinase in the immune system, and more recently have been used to examine the role of this kinase in central nervous system disorders.

The p38 mitogen activated protein (MAP) kinase is an integral enzyme involved in the production of a wide variety of pro-inflammatory cytokines from various cell types. The identification of this kinase and of the diaryl imidazole containing inhibitor, SB203580, initiated an intense discovery effort in this field. Numerous inhibitors were subsequently produced containing replacements for the imidazole, as well as some of the pharmacophores attached to it. During this time many other classes of potent p38 inhibitors emerged containing scaffolds and binding components not found in the diaryl imidazole group. This review summarizes nine of those classes. At least one of these classes requires the kinase to undergo reorganization prior to binding. From this diverse set of inhibitors four compounds have been reported advancing into human clinical trials.

Protein kinases (Ser / Thr and Tyr) play a key role in signal transduction pathways. It has been shown that deregulation of the Cdk activity is linked to cell proliferation and cancer. Inhibition of cyclin-dependent kinases (Cdks) is an important target for potential new anti-cancer drugs. Following the discovery of Olomoucine, a wide range of tri-substituted purine derivatives have been synthesized, leading to potent Cdk inhibitors. These purine-derived compounds bind to the ATP pocket of the protein. Of interest for structurebased drug design, the different crystal structures published to date show evidence for three different binding modes for the purine ring, allowing diverse exploration of the ATP binding site. Some examples of synthesis and structure activity relationships are discussed for a set of purine derivatives, tri-substituted on C-2, N-9 and C-6. Finally, in vivo activities are reviewed, as well as the applications in other therapeutic areas.

The first potent selective small molecule inhibitor of a protein kinase was reported in 1994 by Parke- Davis. PD-153035, 4-(3-bromoanilino)-6,7-dimethoxyquinazoline, is an ATP competitive inhibitor of the epidermal growth factor receptor tyrosine kinase (EGFr), with no appreciable inhibitory activity against several other kinases. Subsequent structural elaboration of PD-153035 led to several 4-anilinoquinazolines that are currently in various stages of clinical trials for the treatment of kinase-mediated diseases.A homology model of EGFr with PD-153035 suggested that the 3-nitrogen atom of the quinazoline ring binds a water molecule. It was envisioned that this nitrogen atom could be replaced by a carbon atom containing an electron-withdrawing group. This critical observation by a group at Wyeth led to the identification of 4-(3- bromoanilino)-6,7-dimethoxy-3-quinolinecarbonitrile as an EGFr inhibitor. It was subsequently established that variation of the substituents on the 4-anilino group of the 6,7-dimethoxy-3-quinolinecarbonitrile changed the kinase specificity from EGFr to other kinases including Src and MEK. The 3-quinolinecarbonitrile template was also utilized to develop an irreversible inhibitor of EGFr, EKB-569, currently in clinical trials for the treatment of cancer.Further manipulation of the 3-quinolinecarbonitrile core provided tricyclic analogs, with the most potent kinase inhibitory activity observed with a benzo[g]quinoline-3-carbonitrile ring system. It was also found that 3-quinolinecarbonitriles with a 7-thiophene or phenyl substituent were potent Src kinase inhibitors.