Advances in Anticancer Agents in Medicinal Chemistry

Protein kinase CK2 (Casein Kinase 2) is an ubiquitous, highly pleiotropic, constitutive active and essential protein kinase, with both cytosolic and nuclear localization in most mammalian cells. The holoenzyme is generally composed of two catalytic (alpha and/or alpha') and two regulatory (beta) subunits, but the free alpha/alpha' subunits are catalytically active by themselves and can be present in cells under some circumstances. CK2 catalyzes the phosphorylation of more than 300 substrates characterized by multiple acidic residues surrounding the phosphor-acceptor amino acid and, consequently, it plays a key role in several physiological and pathological processes. It’s abnormally high constitutive activity is implicated in several diseases and neoplasia, and a number of ATP competitive inhibitors of CK2 with micromolar and nanomolar in vitro activity, display a pro-apoptotic effect also in cell.

Protein kinase B (PKB or Akt) is a central component of the PI3K – PKB – mTOR signaling cascade and is firmly established as an attractive target for pharmacological intervention in cancer. A number of small molecule inhibitors with well-defined, direct molecular interactions with PKB are now known, covering a range of mechanisms from ATP- or substrate-competitive inhibition, through allosteric modulation of the kinase activity, to inhibition of the phosphatidylinositol-dependent activation process. The development of small molecule inhibitors of PKB has benefited greatly from the application of structural biology techniques, particularly for lead generation and the optimisation of compound potency and selectivity. The development of the major chemical series of PKB inhibitors will be outlined, with an emphasis on the application of structure-based design and the strategies used to optimise compound pharmacodynamics, efficacy and therapeutic window. The development of small molecules targeting PKB for anticancer therapy has reached an exciting stage, with the first selective inhibitors entering clinical trials, and several additional chemotypes demonstrating efficacy in preclinical models.

Mammalian target of rapamycin (mTOR) is the hub of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway, which is one of the most commonly mutated pathways in cancer. mTOR is considered a member of the PI3K-kinase-related kinase (PIKK) superfamily since its C-terminus shares strong homology to the catalytic domain of PI3K. Currently it is known that mTOR functions as two complexes, mTOR complex 1 (mTORC1) and mTORC2. Clinically used rapamycin and rapalogs are allosteric inhibitors of mTORC1 and effective as anticancer agents in various preclinical models. In clinical trials, rapalogs have demonstrated efficacy against certain types of cancer. Recently, a new generation of mTOR inhibitors, which compete with ATP in the catalytic site of mTOR and inhibit both mTORC1 and mTORC2 with a high degree of selectivity, have been developed. Besides, some natural products, such as epigallocatechin gallate (EGCG), caffeine, curcumin, resveratrol and cryptotanshinone, have been found to inhibit mTOR as well. Here, we review the current findings regarding mTOR signaling pathway and discuss the advances in mTOR inhibitors as anticancer agents.

One promising therapeutic strategy for treating cancer is to specifically target signal transduction pathways that have a key role in oncogenic transformation and malignant progression. Hsp90 is an emerging therapeutic target of interest for the treatment of cancer. It is responsible for modulating cellular response to stress by maintaining the function of numerous signaling proteins - known as ‘client proteins’ - that are associated with cancer cell survival and proliferation. Many cancers result from specific mutations in, or aberrant expression of, these client proteins. Small molecule Hsp90 inhibitors bind to the ATP binding pocket, inhibit chaperone function and could potentially result in cytostasis or cell death. Consequently, many client proteins are targeted for degradation via the ubiquitin-proteasome pathway including receptor and non receptor kinases (Erb-B2, epidermal growth factor receptor, and Src family kinases), serine/threonine kinases (c-Raf-1 and Cdk4), steroid hormone receptors (androgen and estrogen), and apoptosis regulators such as mutant p53. Inhibition of Hsp90 function Hsp90 has also proven effective in kiling cancer cells that have developed resistance to targeted therapies such as kinase inhibitors.

This review is intended to update recent developments in new Hsp90 inhibitors as antitumors agents, the design, biological evaluation and their clinical trials studies.

Multidrug resistance (MDR) plays the central role in failing cancer therapy regimes of today. The MDR phenomenon concerns various drugs of structurally related as well as unrelated compound classes including also novel anticancer drugs. Formerly drug-sensitive cancer cells lose their sensitivity and become resistant under theapy. Although MDR is a multifactorial process, the main obstacle is the expression of multidrug efflux pumps that lowers the intracellular drug levels by an active drug transport out of the cells. P-glycoprotein (P-gp) is the longest identified efflux pump. The attempt to overcome the MDR phenomenon by the use of inhibitors of the efflux pump activities turned out as most promising beside other so far non-effective tries. So far there exists no X-ray crystal structure analysis of P-gp which is difficult to crystallize because of its transmembrane protein character. Thus, the development of Pgp inhibitors has been a challenge for medicinal chemists. The article reviews advances in P-gp inhibitor development by focussing on structure-activity relationships in the different compound classes to document improvements up today. One success has been the reduction of cytotoxic properties partly resulting from the originally pharmacological compound properties. However, undesired drug interactions and resulting toxicities limited clinical in vivo activities so far.

The kinesin spindle protein (KSP, also known as Hs Eg5) plays an essential role in the proper separation of spindle poles and the correct formation of bipolar mitotic spindle during mitosis. Inhibition of this protein results in cells apoptosis followed by mitotic arrest and the formation of characteristic monoaster spindles. Compared with the traditional chemotherapeutic agents (taxanes, vinca alkaloids), KSP inhibitors (KSPi) will not lead to the neuropathic side effects, so KSP has become a novel and an attractive anticancer target. Accordingly, more and more interest has been focused on the development of high effective and selective KSPi. This review will focus on some kinds of KSPi on the basis of introducing structure and function of KSP.

Current cancer chemotherapy relies heavily on cytotoxic agents, such as the taxanes and Vinca alkaloids, that interfere with the cellular machinery required for cell division and divert the cell down a pathway of programmed cell death. These antimitotic agents, or spindle poisons, target the mitotic spindle by binding to tubulin, a protein required not only for mitosis but also for structural integrity and proper function of healthy, terminally differentiated cells. To avoid side effects attributed to this nonselective mechanism of action, new targets in the mitotic pathway that act only in dividing cells were sought and a leading candidate to emerge from these efforts was kinesin spindle protein (KSP or HsEg5). KSP is a molecular motor protein that is expressed only during mitosis and controls the formation of a functional mitotic spindle. Inhibition of KSP causes mitotic arrest followed by cell death in malignant cells and thus has the potential to become a novel chemotherapeutic strategy with the potential for reduced toxicity. This article summarizes efforts carried out at Merck to discover potent, selective and water soluble KSP inhibitors that culminated in the discovery of MK-0731, the second KSP inhibitor to enter clinical trials. Of special focus in this article is how an HTS lead was optimized in apparently divergent directions, but these disparate leads converged in the design of compounds that overcame P-glycoprotein efflux and hERG channel activity, two issues that required considerable optimization within our program.

Cyclooxygenase-2 (COX-2) oftentimes is highly expressed in cancer tissues, where it supports tumor development and angiogenesis. Over the past 15 years, newly developed non-steroidal anti-inflammatory drugs (NSAIDs) that are able to highly selectively inhibit this enzyme were hoped to become therapeutic tools for cancer prevention and therapy. However, while chemopreventive effects of certain selective COX-2 inhibitors indeed have been documented, their efficacy for therapy of already established cancers has been unimpressive so far. Intriguingly, the investigation of compounds such valdecoxib, rofecoxib, and in particular celecoxib, has revealed molecular targets besides COX-2, and it appears that some of these non-COX-2 targets may be critically involved in mediating the pro-apoptotic effects of these compounds without any apparent involvement of COX-2. In fact, investigations of a series of close structural analogs of celecoxib demonstrated that it is possible to separate COX-2 inhibitory function from apoptosis-stimulatory function within the molecule. For example, 2,5-dimethyl-celecoxib (DMC) has lost COX-2 inhibitory function, yet still exerts profound cytotoxic potency.

This review will summarize pertinent results from the exploratory therapeutic use of NSAIDs, in particular celecoxib, in preclinical and clinical studies of malignant glioma. Several COX-2 independent targets will be presented, and it will be discussed how DMC has helped to delineate their relevance for the surmised COX-2 independent tumoricidal effects of celecoxib.Angiogenesis, azetazolamide, carbonic anhydrase, celecoxib, diclofenac, 2,5-dimethyl-celecoxib (DMC), endoplasmic reticulum stress, etoricoxib, glucose-regulated protein 78 (GRP78), meloxicam, nimesulide, 3- phosphoinositide-dependent protein kinase-1 (PDK1), rofecoxib, temozolomide, valdecoxib.

Histone deacetylase enzymes (HDACs) are epigenetic regulators that remove acetyl groups from the tails of lysine residues of histone protein in nuclear chromatin and also deacetylate some other non-histone proteins. HDACs and histone acetyltransferases (HATs) are major regulators of cellular protein acetylation status; an imbalance in acetylation levels, particularly under-acetylated (hypoacetylated) histone protein has been associated with precancerous or malignant states, arising in part through transcriptional repression induced by regions of condensed chromatin containing non-acetylated, protonated, lysine termini closely bound to DNA phosphate residues. Small-molecule inhibitors of HDACs relieve this transcriptional repression and some are used as clinical anti-cancer agents. The epigenetic level of action of HDAC inhibitors can make them effective against cancers that are refractory to conventional tretament. This review surveys recent developments in the design, structures and biological properties of HDAC inhibitors in the context of potential cancer therapy.

High grade primary CNS gliomas hold some of the worst prognoses of any malignancy, with the vast majority of patients dying within two years of diagnosis, even with aggressive modern treatments. Surgical resection and radiotherapy are cornerstones of treatment when possible. In spite of many years of research, only recently has management with chemotherapy been able to prolong survival in patients with high grade gliomas, albeit only modestly at best. Topoisomerase I (TOP1) inhibitors target an enzyme critical for DNA replication and cell-cycle progression; they cross the blood-brain barrier and have antitumor activity against glioblastoma cells in vitro. The most frequently associated toxicities are neutropenia and diarrhea, but are often manageable. The two most used agents are irinotecan and topotecan. Due to enhanced cytochrome CY3A4/5 enzyme activity, irinotecan dose must be adjusted with concomitant enzyme-inducing antiepileptic drug usage; the data is less clear regarding the effects on topotecan. Clinical trials in patients with recurrent malignant glioma have evaluated TOP1 inhibitors as monotherapy and in combination with other agents. There is evidence for using topotecan with radiotherapy. Irinotecan has limited efficacy as monotherapy, but shows promise in combination with other agents, particularly temozolomide and bevacizumab. Newer generation TOP1 inhibitors are currently being evaluated in phase I trials. TOP1 inhibitors show promising activity in patients with primary CNS malignancies and warrant further study.