Prodrugs of the cancer cell selective anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131) are orally efficacious in a mouse model of resistant colon cancer.

A131 (1) possesses a unique cancer cell selective dual mechanism of action where cancer cells are killed but normal cells only undergo growth arrest and are able to regrow after removal of 1. SAR studies of 1 indicate that only the specific structure of 1 elicits the full pharmacological effect. However, application of 1 in mouse models of cancer has been hampered by its low solubility and stability when given orally. In this work we describe the study of various prodrugs based on modification of the indole nitrogen. A range of acyl analogues were prepared as prodrugs which were shown to undergo degradation to the parent drug in plasma. A preferred prodrug fully elicited the pharmacological effects of 1 in cells and led to high aqueous solubility suitable for oral administration. In a mouse model of paclitaxel-resistant colon cancer, compound 10, as a TFA salt, showed 76% tumor growth inhibition when administered at an oral dose of 80 mg/kg twice a day.

Discovery of the cancer cell selective dual acting anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131).

Selective targeting of cancer cells over normal cells is a key objective of targeted therapy. However few approaches achieve true mechanistic selectivity resulting in debilitating side effects and dose limitation. In this work we describe the discovery of A131 (4a), a new agent with an unprecedented dual mechanism of action targeting both mitosis and autophagy. Compound 4a was first identified in a phenotypic screen in which HeLa cells treated with 4a manifested mitotic arrest along with formation of multiple vesicles. Further investigations showed that 4a causes an increase in mitotic marker pH3 and autophagy marker LC3. Importantly 4a induces cell death in cancer cells while sparing normal cells which regrow after 4a is removed. Dual activities against pH3 and LC3 markers are required for cancer cell selectivity. An extensive SAR investigation confirmed 4a as the optimal dual inhibitor with potency against a panel of 30 cancer cell lines (average antiproliferative GI50 1.5 µM). In a mouse model of paclitaxel-resistant colon cancer, 4a showed 74% tumor growth inhibition when administered at a dose of 20 mg/kg IP twice a day.

Inhibitors of JAK2 and JAK3: an update on the patent literature 2010 - 2012.

INTRODUCTION: Janus kinases (JAKs) comprise a family of four enzymes, JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), centrally implicated in cell signaling processes important in cancer and immune-inflammatory diseases. Progression in the field has taken a recent step forward with the approval of ruxolitinib (Jakafi), a selective inhibitor of JAK1/2 and very recently tofacitinib (Xeljanz), a pan-JAK inhibitor. There are many new JAK family enzyme inhibitors in the clinic now with a range of selectivity profiles. More selective JAK2 or JAK3 compounds are now coming through in considerable numbers and this review attempts to provide an update of the recent patent literature of those new compounds. An overview is given on the diversity of core structures employed for inhibitor design showing that the vast majority of compounds are based on classic ATP-competitive kinase inhibitor heterocycles. AREAS COVERED: This review updates new patents claiming JAK2 and/or JAK3 inhibitors published from 2010 to 2012. Pre-2010 patents have been extensively covered in previous reviews. Comments on the context of each chemical series are given where applicable to orientate the readers on the bewildering array of molecular designs now available. This review does not cover JAK1 or TYK2 inhibitors but mention is made of these where they occur within series of JAK2/3 inhibitors. Given the overlap between many pharmacophores, it was not possible to completely separate inhibitors of JAK2 from JAK3, hence the material is organized by JAK2, JAK3 and JAK2/3 and within each section by alphabetical order of the patent assignee, some companies having published five or more patents, such as Ambit (10), Incyte (9), Galapagos (7), Almirall (6) and Biocryst (5). A total of 98 patents are reviewed herein. EXPERT OPINION: JAK inhibitor therapy is entering a significant new era with the advent on the market of the JAK1/2 inhibitor ruxolitinib and the pan-JAK inhibitor tofacitinib, with unprecedented speed of development. Selectivity against the four individual JAK family enzymes, JAK1, 2, 3 and TYK2, is now a key goal since they each play subtly different roles in cytokine-induced cell signaling. The future looks bright for patients as many new drugs are being developed and now combinations of JAK inhibitors with other targeted agents are being studied in the clinic. These advances are expected to lead to further significant progress improving patient outcomes and quality of life.

Utilizing mobile networks for the detection of clinically relevant interactions between chemotherapy regimens and complementary and alternative medicines.

OBJECTIVES: Patients with cancer who use complementary and alternative medicines (CAMs) in conjunction with chemotherapy treatment are at risk of manifesting anticancer drug-CAM interactions (DCIs), which may lead to negative therapeutic outcomes. This article describes a novel iPhone application developed for the Mobile Internet, called OncoRx-MI, which identifies DCIs of single-agent and multiple-agent chemotherapy regimen (CReg) prescriptions. METHODS: Drug-, CAM-, and DCI-related information was compiled from various hardcopy and softcopy sources, and published literature from PubMed. Overall management plans for the CRegs were then developed. The iPhone Web documents were constructed using Adobe software and programming scripts, and mounted onto a third-party server. DCI searches are based on CReg acronyms, and OncoRx-MI is designed to fit the iPhone screen configuration for improved usability. A small usability study was also carried out and the user feedback presented. RESULTS: OncoRx-MI is able to detect over 2700 interactions between 256 CRegs and 166 CAMs, making up a total of over 4400 DCI pairs. The CAMs are classified into seven categories based on their uses in supportive care, and non-cancer-related CAMs are also included. The majority of the DCIs are pharmacokinetic in nature (79%), involving the induction and inhibition of the cytochrome P450 isozymes and p-glycoprotein. Pharmacodynamic DCIs include hepatotoxicity (39%), altered corticosteroid efficacies (30%), and increased risks of hypoglycemia (4%), hypertensive crisis (2%), bleeding, and serotonin syndrome (1% each). CONCLUSIONS: OncoRx-MI is the first mobile application of its kind that allows searching of DCIs for CRegs through 3G networks, and is intended to improve pharmaceutical care of patients with cancer by assisting health care practitioners in managing CReg interactions in their clinical practices.

Clinically-relevant chemotherapy interactions with complementary and alternative medicines in patients with cancer.

Complementary and alternative medicines (CAMs), in particular herbal medicines, are commonly used by cancer patients in conjunction with chemotherapy treatment for their anticancer properties and supportive care. However, the effects of many of these herbs are not well-documented due to limited studies done on them. Severe herb-drug interactions (HDIs) have been recorded in some cases, and failure to recognize these harmful HDIs can lead to dire consequences in cancer patients. This study discusses clinically-relevant interactions between anticancer drugs (ACDs) and herbs classified into 7 categories: cancer treatment and prevention, immune-system-related, alopecia, nausea and vomiting, peripheral neuropathy and pain, inflammation, and fatigue. Some promising patents which contain these herbs and thus may manifest these interactions are also presented in this article. Pharmacokinetic interactions involved mainly induction or inhibition of the cytochrome P450 isozymes and p-glycoprotein, while pharmacodynamic interactions were related to increased risks of central nervous system-related effects, hepatotoxicity and bleeding, among others. Clinicians should be vigilant when treating cancer patients who take CAMs with concurrent chemotherapy since they face a high risk of HDIs. These HDIs can be minimized or avoided by selecting herb-drug pairs which are less likely to interact. Furthermore, close monitoring of pharmacological effects and plasma drug levels should be carried out to avoid toxicity and ensure adequate chemotherapeutic coverage in patients with cancer.