Recent Patents on Anti-Cancer Drug Discovery - Volume 1, Issue 3, 2006

The c-Myc oncoprotein is a master regulator of genes involved in diverse cellular processes. Situated upstream of signalling pathways regulating cellular replication/growth as well as apoptosis/growth arrest, c-Myc may help integrate processes determining cell numbers and tissue size in physiology and disease. In cancer, this ‘dual potential’ allows c- Myc to act as its own tumour suppressor. Evidently, given that deregulated expression of c-Myc is present in most, if not all, human cancers (Table 1) and is associated with a poor prognosis, by implication these in-built ‘failsafe’ mechanisms have been overcome. To explore the complex activity of c-Myc and its potential as a therapeutic target ‘post-genome era’ technologies for determining global gene expression alongside advanced new models for the study of tumourigenesis in vivo have proved invaluable. Thus, many recent studies have provided encouragement for the therapeutic targeting of c-Myc in cancer and have revealed new protein targets for manipulating aspects of c-Myc activity. The remarkable regression of even advanced and genetically unstable tumours, seen following deactivation of c-Myc in various models is particularly exciting. This review will discuss what is known about the role of c-Myc in growth deregulation and cancer and will conclude with a discussion of the most promising recent developments in Myc-targeted therapeutics.

Mitochondria are proving to be worthy targets for activating specific killing of cancer cells in tumors and a diverse range of mitochondrial targeted drugs are currently in clinical trial to determine their effectiveness as anti-cancer therapies. The mechanism of action of mitochondrial targeted anti-cancer drugs relies on their ability to disrupt the energy producing systems of cancer cell mitochondria, leading to increased reactive oxygen species and activation of the mitochondrial dependent cell death signaling pathways inside cancer cells. We propose that this emerging class of drugs be called “mitocans”, a term that reflects their mitochondrial targeting and anti-cancer roles. They are discussed in this review in the context of their mode of action whereby they target the functional differences and altered properties of the mitochondria inside cancerous but not normal cells. Hence, mitocans include drugs affecting the following mitochondrial associated activities: hexokinase inhibitors; electron transport/respiratory chain blockers; activators of the mitochondrial membrane permeability transition pore targeting constituent protein subunits, either the voltage dependent anion-selective channel (VDAC) or adenine nucleotide transporter (ANT); inhibitors of Bcl-2 anti-apoptotic family proteins and Bax/Bid pro-apoptotic mimetics. In particular, a recent surge has occurred in the number of patent documents describing small molecule inhibitors and BH3 mimetic blockers of Bcl-2/Bcl-xL function as obvious and important targets for promoting mitochondrial induced cancer cell death and for enhancing the actions of other chemotherapeutic agents. One of the other highly significant results to emerge from clinical applications of mitochondrial targeted drugs as cancer therapies to date is that they have shown limited side-effects on the normal “healthy” cell populations in vivo. It is still too early to judge the clinical impact that mitocans will make in treating cancer. Further clinical studies will be required before these novel drugs become established as single modality anti-cancer therapies or are used in conjunction with existing chemotherapies. However, it is clear from the present studies that mitocans offer great potential as effective and exciting new developments in cancer therapy, providing direct activation of cancer cell death by mitochondrial mediated apoptosis and that this complements the other pathways by which existing treatments kill cancer cells. Undoubtedly, mitocans will become an integral part of modern weaponry in the fight to eliminate cancer.

The first line therapy for chronic myeloid leukemia (CML) was dramatically altered within a few years of the introduction of Abl specific tyrosine kinase inhibitor, imatinib mesylate to the clinic. However, refractoriness and early relapse have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the Abl kinase domain that interfere with imatinib mesylate binding are most critical cause of imatinib resistance. To override resistance, several second generation ATP competitive Abl kinase inhibitors such as dasatinib, nilotinib and INNO-406 have been developed. Although, these novel inhibitors can inhibit the phosphorylation of most mutated Bcr-Abl except T315I, no ATP competitive Abl kinase inhibitors, which can inhibit the phosphorylation of Bcr-Abl/T315I, has been developed. Thus, Bcr-Abl/T315I is an important and challenging target for discovery of CML therapeutics. This review is focused on the three novel compounds reported in the recent patents (2004-2006) which claim the efficacy against Bcr- Abl/T315I.

The cyclin dependent kinases, Cdks, are potential targets for new anticancer therapy. Dysregulation of the cell cycle is common during tumorigenesis, and inhibition of certain Cdks has been shown to inhibit tumor cell growth, induce apoptosis and cause tumor regressions in animal models. This review discusses the rationale for inhibiting Cdks as an approach to cancer therapy and the status of Cdk inhibitors in clinical trials. Compounds resulting from a patent literature search from 2003 to July, 2005 are discussed.

Bioactive lipid mediators are increasingly being recognized as important endogenous regulators of cell activation, signaling, apoptosis and proliferation. Most of these lipid mediators are originated from cleavage of constituents of cellular membranes under the activity of phospholipases and sphingomyelinases. One of the major cascades of bioactive lipid mediator production involves the release of arachidonic acid from membrane phospholipids followed by the formation of eicosanoids (i.e. prostaglandins, leukotrienes and lipoxins). These biologically active metabolites of arachidonic acid are emerging as key regulators of cell proliferation and neo-angiogenesis and agents that specifically target these lipid mediators are being investigated as potential anticancer drugs. On the other hand, the lysophospholipid family, which includes members of the sphingomyelin-ceramide-sphingosine-1-phosphate and lysophosphatidic acid subfamilies, has evolved as an important group of lipid signaling molecules implicated in cellular differentiation, cell growth and apoptosis. This article reviews the most recent patents in this field of research, covering the following strategies based on the modulation of bioactive lipid mediators: (1) prostaglandin H synthase-2 inhibitors, (2) lipoxin analogs and aspirin-triggered lipid mediators, and (3) lysophosphatidic acid and other lysophospholipids.

Bisphosphonate (BPs) therapy has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that BPs exert their direct or indirect antitumoral effects on cancer growth factor release, on cancer cell adhesion, invasion and viability, on cancer angiogenesis and on cancer cell apoptosis. Here, after a brief analysis on clinical indications, on the last generation amino-bisphosphonates (N-BP) and on biochemical pathways as molecular targets of BPs, we will discuss the molecular mechanisms of these antitumor effects. Recent evidence suggests that part of the antitumor activity of bisphosphonates may be attributed to an antiangiogenic effect. For this reason, we will analyse all the in vitro and in vivo preclinical reports and the first clinical evidence of antiangiogenic activity exerted by this class of drugs. Several patents have been reported in the review, considering the recents activities observed for these drugs. Taking together all the major results obtained in the described studies, it is possible to affirm that BPs, particularly zoledronic acid and pamidronate, could potentially represent a very powerful tool for angiogenesis inhibition leading to a better control of cancer growth and progression. The translation into the clinical setting of the preclinical evidence of an antiangiogenic power of these drugs is becoming an imperative need and should represent the objective of future clinical trials.

Bortezomib (Velcade, formerly PS-341) represents the first proteasome inhibitor to have shown anti-tumor activity in both solid and haematological malignancies. It blocks activation of nuclear factor-kappa B (NF-κB), resulting in increased apoptosis, decreased angiogenic cytokine production, and inhibition of tumor cell adhesion to stroma. Additional mechanisms of action include c-Jun N-terminal kinase activation, effects on growth factor expression and antiangiogenic properties. Multiple myeloma is the prototype of cancer where bortezomib has shown marked in vitro activity, which was followed by rapid translation to phase I, II and III clinical trials, and resulted in accelerated approval by the FDA for the treatment of patients with relapsed refractory disease. Different clinical trials are currently ongoing in multiple myeloma as well as in many others haematologic and solid tumors (mantle cell and follicular non-Hodgkin's lymphoma; peripheral T-cell lymphoma; Waldenström's macroglobulinemia, chronic lymphocytic leukemia; head and neck / gastroesophageal junction / stomach /colo-rectal / prostate / non-small cell lung cancer). This reviews focuses on the proteasome inhibition exerted by bortezomib, the first proteasome inhibitor to have shown anti-cancer activity in both solid and haematologic malignancies.