Recent Patents on Anti-Cancer Drug Discovery - Volume 11, Issue 3, 2016

Background: Results of long-term studies justify that the rate of breast cancer recurrence and tumor-related mortality remains quite unpredictable, regardless of the use of any current therapeutic measures. Objective: Since the application of standard therapies, such as surgery, radiation, chemotherapy and antiestrogen administration does not work as might be expected; our therapeutic practice requires thorough rethinking. Method: Published long-term therapeutic results on breast cancer cases were analyzed in correlation with stage at diagnosis, ER-status of tumors and patients’ age. The effectiveness of current therapeutic measures was also compared by estimating the rate of tumor-free survival, breast cancer recurrence and breast cancer-specific mortality. Results: Diagnosis and treatment of breast cancer at an early stage cannot improve the rate of tumor-free survival. Poor differentiation of tumors, ER-negativity in particular, defines poor prognosis even after applying aggressive therapies. In patients treated with in situ breast cancer, the recurrence-rate of invasive tumor increased directly with ageing irrespective of tumor size or ER-status at diagnosis. Women who underwent lumpectomy without adjuvant radiation or chemotherapy exhibited significantly better overall and breast cancer specific survival rates than those receiving mastectomy, regardless of stage and ER-status of tumors. Antiestrogen treatment exhibited unforeseeable effectiveness even on targeted ERpositive tumors. Recent patents propose the detection of ESR1-gene amplification or restoration of ER-alpha expression for prediction of effective antiestrogen treatment, suggesting a crucial inhibitory role of estrogen-signaling against tumorgrowth. Conclusion: Estradiol-induced upregulation of estrogen signaling coupled with sparing of the estrogen-rich mammary fatpad are the most effective strategies against breast cancer.

Emerging evidence suggests that human epidermal growth factor receptor 3 plays a critical role in cell-survival and drug-resistance in cancer cells. Several kinds of agents targeting this receptor are currently progressing through preclinical or clinical investigations. These agents are usually monoclonal antibodies with unique characteristics, and some have shown efficacy and been welltolerated in clinical trials. For example, patritumab and seribantumab are thought to compete with ligand binding and have proven efficacy for some malignancies in Phase II clinical trials. LJM716 locks the human epidermal growth factor receptor 3 in the inactive conformation in both ligand-dependent and - independent cancers. Lumretuzumab is a glycoengineered antibody, which enhances antibody-dependent cell-mediated cytotoxicity. Duligotumab is an antibody that targets both the human epidermal growth factor receptors 1 and 3. Heregulin is a human epidermal growth factor receptor 3 ligand that represents an encouraging candidate biomarker for the prediction of the efficacy of agents targeting this receptor. Conclusion: A number of antibodies that interact with human epidermal growth factor receptors have been evaluated for clinical use. Ongoing clinical trials will address the remaining issues related to optimization of drug combination therapy and improving the targeting of each agent to the most appropriate individuals.

Background: Medullary thyroid carcinoma (MTC) originates from the parafollicular C cells of the thyroid gland. Mutations of the RET proto-oncogene are implicated in the pathogenesis of MTC. Germline activating mutations of this gene have been reported in about 88–98% of familial MTCs, while somatic mutations of RET gene have been detected in about 23-70% of sporadic forms. Although these genetic events are well characterized, much less is known about the role of epigenetic abnormalities in MTC. Objective: The present review reports a detailed description of epigenetic abnormalities (DNA methylation, histone modifications and miRNA profile), probably involved in the pathogenesis and progression of MTC. Methods: A systematic review was performed using Pubmed and Google patents databases. Results: We report the current understanding of epigenetic patterns in MTC and discuss the potential use of current knowledge in designing novel therapeutic strategies through epigenetic drugs, focusing on recent patents in this field. Conclusion: Taking into account the reversibility of epigenetic alterations and the recent development in this field, epigenetic therapy may emerge for clinical use in the near future for patients with advanced MTC.

Background: Constitutive activation of the PI3K/mTOR signaling pathway is observed in most, if not all, breast cancers. Accordingly, many PI3K and/or mTOR inhibitors have entered clinical trials, and completed studies should soon reveal the efficacy of these new drug families in the treatment of cancer patients. Objective: We present the PI3K/Akt/mTOR signaling pathway and the structure and the anti-tumor efficiency of some mTOR inhibitors such as rapalogues and competitive inhibitors, which have entered clinical trials. We also discuss some of the clinical trial results associated with these molecules mainly focusing on studies performed on relapsing breast cancer patients - but not only. Results: Most of the clinical trials with PI3K/mTOR inhibitors alone or in combination with chemotherapies were performed in heavily pre-treated patients and revealed non-negligible amounts of partial responses and long-term stable disease for these patients. Therefore, these compounds seem to prevent tumor growth and survival of cancer cells in Human, representing a new range of anti-tumor drugs that can be utilized not only as first-line treatments but as second- and third-line agents for patients who relapse. Conclusion: Drugs inhibiting the PI3K/mTOR signaling pathway may represent tailored anti-tumor agents, paving the way for their clinical application in different tumor types.

Background: The aerobic glycolysis in tumor cells known as Warburg effect is one of the most important hallmarks of cancer. It is proposed that the upregulation of the series of metabolic enzymes along the glycolytic pathway may contribute to the Warburg effect. Objectives: The inhibition of these glycolytic enzymes has been found to be a novel strategy for anticancer treatment. This review summaries recent patents in the development of small molecule inhibitors for the key enzymes in tumor glycolysis. The targeted enzymes are GLUTs, HKs, PFK, PGAM1, PKM2, LDHA, MCTs and PDK. Conclusion: Although most inhibitors are still in the preclinical phase, the inhibition of glycolytic enzymes represents a very promising approach for anticancer treatment. The future development could be more focused on the discovery of new metabolic enzyme that is specifically expressed in tumor cells.

This review, of the literature published between 2010 and 2015 reports that molecules containing a non-fused and/or fused pyrazole moiety could exhibit very potent activity toward Pim kinases, including the inhibition of cellular Bad phosphorylation as well as antiproliferative activity against various cancer cells. Even if Pim kinase inhibitors currently in clinical trial do not exhibit a pyrazole moiety, heteroaromatic kinase inhibitors containing an indazole part such as Axitinib and Pazopanib already reached the market. Therefore, one can imagine that in the future, heteroaromatic derivatives inhibiting Pim kinases including pyrazoles could be identified and used for their diagnostic and/or therapeutic potential alone or in combination with other drugs for the diseases in which Pim kinases are involved.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. However, the inherent limitations of traditional surgery and insensitivity to radiation and chemotherapy result in failing treatment and poor prognosis. In recent years, the development and advances of nanotechnology has brought new hope for the diagnosis and treatment of HCC. This article reviews the development of nanoparticles used for cancer detection, diagnosis and treatment due to their large specific surface area and unique optical, electronic and magnetic properties. Moreover, studies have shown that after intended surface modification, nano-carriers can achieve active targeting effect, which improves the efficiency of chemotherapeutic drugs and decreases their side effects. In this review, we provide an overview of these studies results, patents about novel nanomaterials and conclude with a discussion about future development.

Recent studies show that enhanced mitochondrial biogenesis can “fuel” the cancer cells to grow and migrate. It is therefore proposed that inhibiting the mitochondrial biogenesis could be a new approach to cancer therapy. This review summarizes recent patents and papers in the development of small molecule inhibitors of key regulators responsible for tumor mitochondrial biogenesis, including PPARγcoactivator-1α(PGC-1α), PPARγcoactivator-1β, estrogen-related receptor family (ERRs), estrogen receptor α(ERα), mammalian target of rapamycin, c-Myc and PPARs.

Background: Curcumin is a polyphenolic natural compound with multiple targets that used for the prophylaxis and treatment of some type of cancers like cervical and pancreatic cancers. Some recent patent for curcumin for cancer has also been reviewed. Objective: In this study, ten new curcumin derivatives were designed and synthesized and their cytostatic activity evaluated against the Hela and Panc cell lines that some of them showed more activity than curcumin. Method: In the present study, a series of mono-carbonyl derivatives of curcumin were designed and prepared. The details of the synthesis and chemical characterization of the synthesized compounds are described. The cytostatic activities of the designed compounds are assessed in two different tumor cell lines using MTT test. Results: In vitro screening for human cervix carcinoma cell lines (Hela) and pancreatic cell lines (Panc-1) at 24 and 48 hour showed that all the analogs possessed good activity against these tumor cell lines and compounds 5a, 5c and 6 with high potency can be used as a new lead compounds for the designing and finding new and potent cytostatic agents. Docking studies indicated that compound 5c readily binds the active site of human glyoxalase I protein via two strong hydrogen bonds engaging residues of Glu-99 and Lys-156. Conclusion: Our results are useful in guiding a design of optimized ligands with improved pharmacokinetic properties and increased of anti-cancer activity vs. the prototype curcumin compound.