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cancer drug discovery

Jimin Xu, Eric A Wold, Ye Ding, Qiang Shen, Jia Zhou
Oridonin, a diterpenoid natural product commonly used in East Asian herbal medicine, is garnering increased attention in the biomedical community due to its extensive biological activities that include antitumor, anti-inflammatory, antimicrobial, hepatic fibrosis prevention, and neurological effects. Over the past decade, significant progress has been made in structure activity relationship and mechanism of action studies of oridonin for the treatment of cancer and other diseases. This review provides a brief summary on oridonin and its analogs in cancer drug discovery and antiinflammation and highlights its emerging therapeutic potential in neuroprotection applications...
February 22, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Iwao Ojima, Xin Wang, Yunrong Jing, Changwei Wang
Paclitaxel and docetaxel are among the most widely used chemotherapeutic drugs against various types of cancer. However, these drugs cause undesirable side effects as well as drug resistance. Therefore, it is essential to develop next-generation taxoid anticancer agents with better pharmacological properties and improved activity especially against drug-resistant and metastatic cancers. The SAR studies by the authors have led to the development of numerous highly potent novel second- and third-generation taxoids with systematic modifications at the C-2, C-10, and C-3' positions...
February 22, 2018: Journal of Natural Products
Junjian Wang, Shaoxiang Huang
Lung cancer is the most prevalent malignant tumor type in the developed world and the discovery of novel anti-tumor drugs is a research hotspot. Fisetin, a naturally occurring flavonoid, has been reported to have anti-cancer effects in multiple tumor types. The present study found that fisetin inhibited the growth and migration of non-small cell lung cancer in vitro . MTT, wound-healing, cell-matrix adhesion and Transwell assays were performed and demonstrated that fisetin suppressed proliferation, migration, adhesion and invasion, respectively...
March 2018: Experimental and Therapeutic Medicine
Guangwei Wu, Xin Qi, Xiaomei Mo, Guihong Yu, Qiang Wang, Tianjiao Zhu, Qianqun Gu, Ming Liu, Jing Li, Dehai Li
DNA topoisomerase I (Topo I) is an important anticancer drug target, and xanthone dimers are considered to be a new kind of Topo I inhibitor chemotypes. Based on the characteristics of dimeric xanthone structures, five new dimeric xanthones (1-5) and two known SAD isomers (6 and 7) were isolated from the mangrove-derived fungus Aspergillus vericolor. The absolute configurations of compounds 1-7, entailing both central and axial chirality elements, were established by a combination of ECD comparison, chemical conversions, and biogenetic considerations...
February 13, 2018: European Journal of Medicinal Chemistry
Hao Zhang, Jin Wang, Ying Shen, Hui-Yan Wang, Wei-Ming Duan, Hong-Yi Zhao, Yuan-Yuan Hei, Minhang Xin, Yong-Xiao Cao, San-Qi Zhang
Targeting acquired drug resistance is the major challenge in the treatment of EGFR-driven non-small cell lung cancer (NSCLC). In this study, a novel class of compounds containing pyrido[3,4-d]pyrimidine scaffold was designed as new generation EGFR-TKIs to overcome this challenge. The most promising compound B30 inhibited HCC827 and H1975 cells growth with the IC50 values of 0.044 μM and 0.40 μM, respectively. Meanwhile, B30 displayed potent inhibitory activity against the EGFRL858R (IC50  = 1.1 nM) and EGFRL858R/T790M/C797S (IC50  = 7...
February 16, 2018: European Journal of Medicinal Chemistry
Charles Samuel Umbaugh, Adriana Diaz-Quiñones, Manoel Figueiredo Neto, Joseph J Shearer, Marxa L Figueiredo
Laminin receptor (67 LR) is a 67 kDa protein derived from a 37 kDa precursor (37 LR). 37/67 LR is a strong clinical correlate for progression, aggression, and chemotherapeutic relapse of several cancers including breast, prostate, and colon. The ability of 37/67 LR to promote cancer cell aggressiveness is further increased by its ability to transduce physiochemical and mechanosensing signals in endothelial cells and modulate angiogenesis. Recently, it was demonstrated that 37/67 LR modulates the anti-angiogenic potential of the secreted glycoprotein pigment epithelium-derived factor (PEDF)...
January 19, 2018: Oncotarget
Kriti Singh, Ravi S N Munuganti, Nada Lallous, Kush Dalal, Ji Soo Yoon, Aishwariya Sharma, Takeshi Yamazaki, Artem Cherkasov, Paul S Rennie
Estrogen receptor-α positive (ERα⁺) breast cancers represent 75% of all invasive breast cancer cases, while de novo or acquired resistance to ER-directed therapy is also on the rise. Numerous factors contribute to this phenomenon including the recently-reported ESR1 gene mutations such as Y537S, which amplifies co-activator interactions with ERα and promotes constitutive activation of ERα function. Herein, we propose that direct targeting of the activation function-2 (AF2) site on ERα represents a promising alternative therapeutic strategy to overcome mutation-driven resistance in breast cancer...
February 15, 2018: International Journal of Molecular Sciences
Ming-Ju Chou, Hsing-Yi Yu, Jui-Ching Hsia, Ying-Hou Chen, Tzu-Ting Hung, Hsiao-Mei Chao, Edward Chern, Yi-You Huang
Intracellular protein delivery may provide a safe and non-genome integrated strategy for targeting abnormal or specific cells for applications in cell reprogramming therapy. Thus, highly efficient intracellular functional protein delivery would be beneficial for protein drug discovery. In this study, we generated a cationic polyethyleneimine (PEI)-modified gelatin nanoparticle and evaluated its intracellular protein delivery ability in vitro and in vivo. The experimental results showed that the PEI-modified gelatin nanoparticle had a zeta potential of approximately +60 mV and the particle size was approximately 135 nm...
February 15, 2018: Materials
Safia Manzoor, Aishah Bilal, Sardraz Khan, Rahim Ullah, Sunniya Iftikhar, Abdul-Hamid Emwas, Meshari Alazmi, Xin Gao, Ali Jawaid, Rahman Shah Zaib Saleem, Amir Faisal
Microtubules are highly dynamic structures that form spindle fibres during mitosis and are one of the most validated cancer targets. The success of drugs targeting microtubules, however, is often limited by the development of multidrug resistance. Here we describe the discovery and characterization of SSE15206, a pyrazolinethioamide derivative [3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide] that has potent antiproliferative activities in cancer cell lines of different origins and overcomes resistance to microtubule-targeting agents...
February 19, 2018: Scientific Reports
Chuantao Zha, Wenjia Deng, Yan Fu, Shuai Tang, Xiaojing Lan, Yan Ye, Yi Su, Lei Jiang, Yi Chen, Ying Huang, Jian Ding, Meiyu Geng, Min Huang, Huixin Wan
CDK4/6 pathway is an attractive chemotherapeutic target for antitumor drug discovery and development. Herein, we reported the structure-based design and synthesis of a series of novel tetrahydronaphthyridine analogues as selective CDK4/6 inhibitors. Compound 5 was identified as a hit and then systematically structure optimization study was conducted. These efforts led to compound 28, which exhibited excellent in vitro potencies against CDK4/6 enzymatic activity with high selectivity over CDK1, and against Colo-205 cell growth...
February 12, 2018: European Journal of Medicinal Chemistry
Alexander B Sigalov
Intramembrane protein-protein interactions (PPIs) are involved in transmembrane signal transduction mediated by cell surface receptors and play an important role in health and disease. Recently, receptor-specific modulatory peptides rationally designed using a general platform of transmembrane signaling, the signaling chain homooligomerization (SCHOOL) model, have been proposed to therapeutically target these interactions in a variety of serious diseases with unmet needs including cancer, sepsis, arthritis, retinopathy, and thrombosis...
2018: Advances in Protein Chemistry and Structural Biology
D Thirumal Kumar, P Sneha, Jennifer Uppin, S Usha, C George Priya Doss
Protein-protein interaction (PPI) helps in maintaining the cellular homeostasis. In particular, the homodimeric proteins play a crucial role as cell regulators. Studying the critical functions of each PPI on the living system is very challenging. The mutations in the PPIs have given birth to various diseases including many types of cancers and it has soon become the target for drug discovery. The mutations in IDH1, an asymmetric homodimer in the cytoplasm, leads to various diseases including gliomas. In this study, we have used extensive computational approaches to identify the impact of missense mutations (R132C, R132G, R132H, R132L, R132S, and V178I) occurring in the interacting region of the IDH1 homodimer...
2018: Advances in Protein Chemistry and Structural Biology
Eduard Stefan, Jakob Troppmair, Klaus Bister
The architectures of central signaling hubs are precisely organized by static and dynamic protein-protein interactions (PPIs). Upon deregulation, these PPI platforms are capable to propagate or initiate pathophysiological signaling events. This causes the acquisition of molecular features contributing to the etiology or progression of many diseases, including cancer, where deregulated molecular interactions of signaling proteins have been best studied. The reasons for PPI-dependent reprogramming of cancer-initiating cells are manifold; in many cases, mutations perturb PPIs, enzyme activities, protein abundance, or protein localization...
2018: Advances in Protein Chemistry and Structural Biology
Martin S Davey, Roshni Malde, Rory C Mykura, Alfie T Baker, Taher E Taher, Cécile S Le Duff, Benjamin E Willcox, Youcef Mehellou
The aryloxy triester phosphoramidate prodrug approach has been used with success in drug discovery. Herein, we describe the first application of this prodrug technology to the monophosphate derivative of the phosphoantigen HMBPP and one of its analogues. Some of these prodrugs exhibited specific and potent activation of Vγ9/Vδ2 T-cells, which were then able to lyse bladder cancer cells in vitro. This work highlights the promise of this prodrug technology in the discovery of novel immunotherapeutics.
February 19, 2018: Journal of Medicinal Chemistry
Aletta E van der Westhuyzen, Liliya V Frolova, Alexander Kornienko, Willem A L van Otterlo
Rigidins (2-6) are pyrrolopyrimidine alkaloids isolated from marine tunicates. Since their isolation, refinement of their total syntheses, and biochemical evaluation, interest toward this pyrrolo[2,3-d]pyrimidine scaffold as a medicinal candidate has been triggered. The derivatization of these natural products has led to the discovery of a novel range of 7-deazahypoxanthines, which exhibit extremely potent anticancer activity in human cancer cell lines. A major breakthrough toward the synthesis of rigidin and various rigidin analogues has been the application of multicomponent reactions (MCRs)...
2018: Alkaloids. Chemistry and Biology
Khushwant S Bhullar, Naiara Orrego Lagarón, Eileen M McGowan, Indu Parmar, Amitabh Jha, Basil P Hubbard, H P Vasantha Rupasinghe
The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer...
February 19, 2018: Molecular Cancer
Bindu Madhuri Cavuturu, Vishwambar Vishnu Bhandare, Amutha Ramaswamy, Neelakantan Arumugam
By virtue of their regulatory role in the biological process, certain protein-protein complexes form potential targets for designing and discovery of drugs. Alteration set in the controlled formation of such complexes results in dysregulation of several metabolic processes, leading to diseased condition. β-catenin/Tcf4 complex is one such protein-protein complex found altered in colorectal epithelial cells resulting in activation of target genes leading to cancer. Recently certain lignans from seeds of the oil crop sesame were found inhibiting initiation and progression of this type of cancer...
February 18, 2018: Journal of Biomolecular Structure & Dynamics
Khushboo Agrawal, Viswanath Das, Pankhuri Vyas, Marián Hajdúch
DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of cancer-related genes. Since the relationship between aberrant DNA methylation and cancer has been understood, there has been an explosion of research at developing anti-cancer therapies that work by inhibiting DNA methylation. From the discovery of first DNA hypomethylating drugs in the 1980s to recently discovered second generation pro-drugs, exceedingly large number of studies have been published that describe the DNA hypomethylation-based anti-neoplastic action of these drugs in various stages of the pre-clinical investigation and advanced stages of clinical development...
February 15, 2018: Pharmacology & Therapeutics
Rand Shahin, Iman Mansi, Lubna Swellmeen, Tahani Alwidyan, Nabil Al-Hashimi, Yaser Al-Qarar'h, Omar Shaheen
Targeting tropomycin kinase A (TrkA) by small molecule inhibitors is considered as a promising strategy for treating several human cancers. To achieve this goal, a ligand based QSAR model was applied using the Discovery studio 4.5 (DS 4.5). Hence, a total list of 161 TrkA inhibitors was investigated. The TrkA inhibitors were extensively explored to detect their optimal physicochemical properties and pharmacophoric binding modes, which were converted into numeric descriptors and allowed to compete within the context of the Genetic Function Algorithm (GFA) approximations to find the subset of terms that correlates best with the activity...
January 13, 2018: Journal of Molecular Graphics & Modelling
Katherine M Byrd, Brian S J Blagg
Both Hsp70 and Hsp90 chaperones are overexpressed in cancer, making them relevant targets for the development of cancer chemotherapeutics, but a lack of biomolecular readouts for Hsp70 inhibition has limited the pursuit of specific inhibitors for this enzyme. A new study from Cesa et al. identifies two inhibitors of apoptosis proteins (IAPs) as specific client substrates of Hsp70. These results establish biomarkers that can be utilized to monitor Hsp70 inhibition and provide a framework for future efforts to deconvolute chaperone networks...
February 16, 2018: Journal of Biological Chemistry
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