Recent Patents on Anti-Cancer Drug Discovery - Volume 10, Issue 3, 2015

Several tumors exhibit pH gradient reversal, with acidification of extracellular pH (pHe) and alkalinization of intracellular pH (pHi). The pH gradient reversal is evident even during the preliminary stages of tumorigenesis and is crucial for survival and propagation of tumors, irrespective of their pathology, genetics and origins. Moreover, this hallmark seems to be present ubiquitously in all malignant tumors. Based on these facts, we propose a new emerging hallmark of cancer “pH gradient reversal”. Normalizing pH gradient reversal through inhibition of various proton transporters such as Na+-H+ exchanger (NHE), Vacuolar-type H+-ATPase (V-ATPase), H+/K+-ATPases and carbonic anhydrases (CAs) has demonstrated substantial therapeutic benefits. Indeed, inhibition of NHE1 is now being regarded as the latest concept in cancer treatment. A recent patent deals with the utilization of cis-Urocanic acid to acidify the pHi and induce apoptosis in tumors. Another patent reports therapeutic benefit by inhibiting Lactate Dehydrogenase - 5 (LDH-5) in various cancers. Several patents have been formulated by designing drugs activated through acidic pHe providing a cancer specific action. The purpose of this review is to analyze the available literature and help design selective therapies that could be a valuable adjunct to the conventional therapies or even replace them.

Cabozantinib is an oral once-daily multitarget tyrosine kinase inhibitor of MET, VEGFR2, RET, acting against KIT, AXL, FLT3 and Tie-2. Cabozantinib has shown anti-cancer effects in preclinical and clinical models of cancers derived from both epithelial and mesenchymal origins [prostate cancer, non small lung cancer, medullary thyroid cancer (MTC) and differentiated thyroid cancer (DTC), renal cell carcinoma, etc.]. In a Phase III clinical study, cabozantinib improved PFS (11.2 months versus 4.0 months in the placebo group) of patients with MTC (independently of age, bone metastases, RET status and prior treatment). Cabozantinib was approved in 2012 by FDA for metastatic MTC and in 2013 by EMA. Cabozantinib has been also evaluated in metastatic DTC patients, because they have activation on tyrosine kinases, including MET, VEGFR2 and RET, suggesting the possible use of cabozantinib in metastatic DTC. Actually, two Phase II trials of cabozantinib in DTC patients resistant to RAI are ongoing. To increase the antineoplastic effect of cabozantinib, and to overcome the occurence of drug resistance, combination studies with other anticancer agents are ongoing. In conclusion, cabozantinib has shown to exert an important therapeutic effect in patients with MTC improving PFS. In DTC patients, cabozantinib has shown promising results.

The transcription factor FOXM1 is overexpressed in many human cancers, including liver, stomach, prostate, brain, breast, lung, colon, pancreas, cervix, ovary and nervous system. Recent data have demonstrated that FOXM1 is involved in cell initiation, progression, and metastasis and in responses to anticancer drugs. In this review, the effects of FOXM1 on gastric cancer, especially the function and regulation of FOXM1 in tumorigenesis and clinical chemotherapy, will be summarized and discussed together with recent relevant patents on the role of FOXM1 in tumor therapy.

Cancer is a disease of remarkable importance in the world today and is projected to become the primary cause of death within the coming years, therefore the design and development of new antitumor agents is one of the most pressing research areas in medicinal chemistry. Considering the importance of thiazole ring as scaffold present in a wide range of therapeutic agents, the medicinal chemists have been encouraged to synthesize a large number of novel antitumors bearing this heterocycle, which furnish extensive synthetic possibilities due to the presence of several reaction sites. The present review describes the patents from 2008 to present concerning new thiazole compounds useful for the development of new drug molecules. It has been divided according to the molecular target and describes the pathways involved in the biological activities and the structure of the most potent compounds, together with the screening results.

The formation of a tumor-associated vascular network is an important step in understanding the stages of tumor progression. This review aims to highlight the main markers of induction, proliferation and inhibition of angiogenesis, as well as the quantification of microvessel density, correlated with preclinical and clinical research in gynecologic cancers and also discussed related patents. Studies show that in the most advanced cases of gynecological cancers, biomarkers such as VEGF (Vascular Endothelial Growth Factor), MMP (Matrix Metalloproteinase), CD105 (Endoglin), TIMP (tissue inhibitors of metalloproteinases) and VASH (Vasohibin) are more expressed compared to healthy individuals. Continuous evaluation of these biomarkers in cancer cases could serve in the future as a basis for development of new therapeutic approaches, leading to a good response to cancer treatment, and thus increase survival of cancer patients.

Protein kinases constitute one of the largest and most functionally diverse gene families that regulate key cell functions. In past several years, kinase inhibition has emerged as potential anti-cancer drug target. Purine is a priveleged heterocyclic nucleus which exists in the chemical architecture of various bioactive compounds. Numerous reports on the use of purine analogues in the treatment of acute leukemias (thiopurines, pentostatin), as antiviral (acyclovir, penciclovir, ganciclovir), as immunosuppressive (azathioprine), as antitumor (vidarabine), as bronchodilator (theophylline) have been revealed. In the past decade, purine analogues have emerged as significantly potent kinase inhibitors. A fair amount of research has been done and several patents have also been published highlighting the kinase inhibitory action of purines. Caffeine, 2- aminopurine, purvalanol-A, seleciclib, FSBA, adenosine thiol analogue possessing purine as the basic moiety fall under this category. In view of the use of purines for the inhibition of kinases, there is need for compilation of data specifying the prominence of purines in the treatment of cancer through this mechanism. The structure of the potent compounds, their IC50 values, models used and the enzymes/ receptors/ targets involved have been presented in this review. The present compilation covers the patents published entailing the purines as kinase inhibitors and the purine drugs employed in chemotherapy.

Background: Erlotinib is a validated drug “for the treatment of patients affected by advanced unresectable non small cell lung cancer (NSCLC) with EGFR mutations”. We want to focus on potential functional benefits deriving from a combined therapy containing TKI (erlotinib) and a nicotinic partial agonist (varenicicline) in smokers. Methods: we analyzed the records of patients affected by NSCLC treated undergoing “first line therapy with Erlotinib” and smoking cessation (with varenicicline). Response to therapy was evaluated by CT scan. Data concerning clinical history, smoking habit, nicotine dependence were collected after three months from the beginning of the recruitment. Pulmonary function tests including spirometry with pletismographic technique and exhaled carbon monoxide (CO) were performed with recording of resistances, flows, volumes. A group of ten current smokers affected by NSCLC with EGFR activating mutation and concurrent mild COPD undergoing anti-EGFR treatment without smoking cessation was used to compare clinical and functional data. A control group of NSCLC wild type with mild COPD undergoing smoking cessation was assessed for functional data. Results: Twenty-five patients were enrolled. All of them reported partial response at CT re-evaluation. All functional indexes and parameters were improved after combined treatment a significant increase of FEV1 level and a decrease of exhaled CO. In particular, a mean increase of FEV1 from 1.93 (SD 0.48) to 2.03(SD 0.46) liters was recorded. A notable reduction of sRAW (specific resistances) was also observed. The improvement of some parameters such as CO, heart rate (HR), sRAW and FEV1 resulted statistically significant. A better response to therapy was found “in the study group compared to the second group of mutated NSCLC patients”. In this second group, we also observed an improvement of functional obstructive parameters although it was less remarkable than study group. Only sRAW and FEF 25/75 were significantly increased. The group of NSCLC wild type undergoing only smoking cessation showed a lower increase of FEV1 by about 50 ml compared to the first group. Conclusion: The combination of anti-EGFR treatment and concurrent therapy for smoking cessation seems to be more effective than erlotinib alone in improving lung function and clinical response in advanced NSCLC patients with EGFR-mutations. It is conceivable that erlotinib may potentiate the action of varenicline. We have also outlined some relevant patents concerning varenicline and EGFR-TKI.