Anti-Cancer Agents in Medicinal Chemistry - Volume 7, Issue 6, 2007

Protein tyrosine kinases (PTKs) play important roles in biochemical signaling events related to cellular activation, differentiation, proliferation, and survival. Because of their contribution to chemotherapy resistance as well as growth of human cancers, several PTKs have emerged as new molecular targets in cancer therapy. The reported clinical successes with the anti- HER2 monoclonal antibody Herceptin in breast cancer, anti-EGFRI antibody Erbitux in colon cancer, and small molecule kinase inhibitor Gleevec in BCR-ABL positive leukemias have resulted in a paradigm-shift in treatment of cancer and sparked interest in tyrosine kinase inhibitors as a new class of promising drug candidates. In this issue, we explore the clinical potential of small molecule inhibitors targeting the JAK, SRC, TEC and FAK family of PTK. Many of these drug candidates in the PTK inhibitor pipeline have entered into clinical testing, while others are at advanced preclinical stages. Our issue begins with an overview by Gunby et al. entitled “Oncogenic fusion tyrosine kinases as molecular targets for anti-cancer therapy”. In two of the review articles, the potential of rationally designed selective tyrosine kinase inhibitors targeting JAK3 and BTK are discussed by Uckun, Vassilev, and Tibbles. In the article entitled “Non-Receptor Tyrosine Kinase Inhibitors in Lung Cancer”, Hahn and Salgia discuss the development of tyrosine kinase inhibitors for lung cancer. Godeny and Sayeski review the role of Janus Kinase 2 (Jak2) in both classical cellular signaling and neoplastic growth in “Jak2 Tyrosine Kinase and Cancer: How Good Cells Get HiJAKed”. In their article entitled “Src Family of Non-Receptor Tyrosine Kinases as Molecular Targets for Cancer Therapy”, Johnson and Gallick discuss the potential of SRC kinase inhibitors. Schenone, Manetti and Botta continue the discussion of SRC kinase inhibitors in their article “Synthetic Src-kinase domain inhibitors and their structural requirements”. Finally, in the review entitled “Role of Focal Adhesion Kinase in Human Cancer: A Potential Target for Drug Discovery”, Han and McGonigal discuss FAK kinase inhibitors. We are hopeful that these review articles will serve as a useful reference and guide for readers who are interested in learning more about the role of PTK in cancer biology and the clinical potential of PTK inhibitors.

Deregulated activation of protein tyrosine kinases (PTKs) is a frequent event underlying malignant transformation in many types of cancer. The formation of oncogenic fusion tyrosine kinases (FTKs) resulting from genomic rearrangements, represents a common mechanism by which kinases escape the strict controls that normally regulate their expression and activation. FTKs are typically composed of an N-terminal dimerisation domain, provided by the fusion partner protein, fused to the kinase domain of receptor or nonreceptor tyrosine kinases (non-RTKs). Since FTKs do not contain extracellular domains, they share many characteristics with non-RTKs in terms of their properties and approaches for therapeutic targeting. FTKs are cytoplasmic or sometimes nuclear proteins, depending on the normal distribution of their fusion partner. FTKs no longer respond to ligand and are instead constitutively activated by dimerisation induced by the fusion partner. Unlike RTKs, FTKs cannot be targeted by therapeutic antibodies, instead they require agents that can cross the cell membrane as with non-RTKs. Here we review the PTKs known to be expressed as FTKs in cancer and the strategies for molecularly targeting these FTKs in anti-cancer therapy.

Inhibitors of Janus Kinase 3 (JAK3) show potential as a new class of apoptosis-inducing anti-cancer drugs. In addition, JAK3 inhibitors may also be useful as immunosuppressive agents. Rationally designed selective inhibitors of JAK3 such as JANEX-1, that do not inhibit other Janus kinases have recently undergone extensive preclinical testing that revealed a favorable pharmacodynamic profile. Here we discuss the clinical potential of targeting JAK3-linked signal transduction pathways with small molecule inhibitors such as JANEX-1.

Targeting Bruton's tyrosine kinase (BTK) with a small molecule inhibitor may be useful in treatment of BTK-expressing malignancies because of the anti-apoptotic function of BTK in cancer cells. Furthermore, BTK inhibitors also exhibit anti-thrombotic properties that may be desirable in the context of the increased risk of thromboembolic complications in cancer patients. This review will focus on the role of BTK in drug resistance in cancer, thromboembolism, and various pathologic immune responses, such as graft versus host disease. The therapeutic potential of targeting BTK is illustrated by discussion of the biologic activity profile of the rationally designed BTK inhibitor LFM-A13.

Lung cancer is a leading cause of cancer death. Systemic therapies with cytotoxic chemotherapies remain ineffective. Current research efforts in lung cancer have focused on developing novel agents to target cellular pathways that are altered in lung cancer. Protein tyrosine kinases are a family of oncogenes that regulate important cellular processes such as differentiation, proliferation, cell cycle, motility, and apoptosis. In this article, we review non receptor tyrosine kinases’ role in lung cancer and the development of agents that target these proteins.

Cloned in 1992, Jak2 tyrosine kinase has emerged as a critical molecule in mammalian development, physiology, and disease. Here, we will review the early history of Jak2 as it pertains to its role in classical cellular signaling. We also review how specific structural determinants within Jak2 dictate its overall function. Finally, we will review relatively recent literature as it pertains to the role of Jak2 in neoplastic growth as well as the identification of novel Jak2 inhibitors. It is our hope that by reviewing these specific areas, we will have a better understanding of the role of Jak2 in cancer, and in turn, we may have a better idea as to how to block aberrant Jak2 function.

The Src family of kinases has nine known members, all of which are nonreceptor tyrosine kinases involved in signal transduction in both normal and cancer cells. Interest in these kinases has increased recently because of the development, initial clinical success, and low toxicity of pharmacologic inhibitors. c-Src is the best-studied member of the Src family and the one most often implicated in cancer progression. c-Src has multiple substrates that lead to diverse biologic effects, including changes in proliferation, motility, invasion, survival, and angiogenesis. c-Src has been most extensively studied in colon cancer where correlative and direct experimental evidence has shown that it mediates several aspects of cancer cell progression. c-Src has a similar role in multiple tumor types, including pancreatic cancer, breast cancer, lung cancer, head and neck squamous cell carcinoma, and prostate cancer. Several inhibitors of the Src family kinases are in clinical development; three are currently being studied in clinical trials. Initial data from these trials suggest that these agents are well tolerated. Future clinical development of these inhibitors will include trials in patients with solid tumors and of combination therapy.

Protein tyrosine kinases catalyze the transfer of phosphoryl groups from ATP to amino acids on proteins and play a fundamental role in signal transduction pathways in mammalian cells. In particular, Src and Src-family are non-receptor tyrosine kinases that regulate cell growth, differentiation, migration, adhesion and apoptosis. Src-family members share common features, with well defined domains. The activation of these enzymes in response to a variety of stimuli leads from a close and inactive conformation to an open and active one, through a balance of phosphorylation and dephosphorylation of the enzyme structure, characterized in different cases by Xray crystallography. Overexpression, deregulation or mutations of these enzymes have been observed and studied in many diseases, first of all in many human malignancies, such as colon, breast, pancreatic and other cancers. Src-family is also involved in other pathologic situations, such as osteoporosis, cardiovascular diseases, immune system disorders, and, recently, it has been also demonstrated the involvement of Src in prion diseases.Therefore, Src-family is an attractive and fundamental target for the design of new therapeutic agents against different pathologies, in particular cancer and bone diseases. Currently, there is no approved drug acting as Src kinase inhibitor, but new molecules, very potent and selective toward this family of kinases and also in vivo, are continuously synthesized, as demonstrated by the high number of publications and patents in this field. Here, we report several examples of Src kinase domain inhibitors, focusing our attention on chemical structures, structure-activity relationships and mechanism of action.

The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes to the points of cell contact with the extracellular matrix, called focal adhesions. FAK is involved in several cellular processes including invasion, motility, proliferation and apoptosis. In in vivo animal studies, FAK has been shown to contribute to tumor development and malignancy. Furthermore, FAK expression was shown to be elevated in a number of human cancers. Increased FAK expression and activity are correlated with malignant phenotype and poor prognosis in patients. Taken together, these studies suggest that FAK is a potentially good target for drug discovery. In this review, FAK and its relationship to cancer, as well as approaches to therapeutic intervention of FAK will be discussed.

The disease of cancer has been ranked second after cardiovascular diseases and plant-derived molecules have played an important role for the treatment of cancer. Nine cytotoxic plant-derived molecules such as vinblastine, vincristine, navelbine, etoposide, teniposide, taxol, taxotere, topotecan and irinotecan have been approved as anticancer drugs. Recently, epothilones are being emerging as future potential anti-tumor agents. However, targeted cancer therapy has now been rapidly expanding and small organic molecules are being exploited for this purpose. Amongst target specific small organic molecules, quinazoline was found as one of the most successful chemical class in cancer chemotherapy as three drugs namely Gefitinib, Erlotinib and Canertinib belong to this series. Now, quinazoline related chemical classes such as quinolines and naphthyridines are being exploited in cancer chemotherapy and a number of molecules such as compounds EKB-569 (52), HKI-272 (78) and SNS-595 (127a) are in different phases of clinical trials. This review presents the synthesis of quinolines and naphthyridines derivatives, screened for anticancer activity since year 2000. The synthesis of most potent derivatives in each prototype has been delineated. A brief structure activity relationship for each prototype has also been discussed. It has been observed that aniline group at C-4, aminoacrylamide substituents at C-6, cyano group at C-3 and alkoxy groups at C-7 in the quinoline ring play an important role for optimal activity. While aminopyrrolidine functionality at C-7, 2'-thiazolyl at N-1 and carboxy group at C-3 in 1,8-naphthyridine ring are essential for eliciting the cytotoxicity. This review would help the medicinal chemist to design and synthesize molecules for targeted cancer chemotherapy.