scholarly journals Small Molecule Inhibitors of HSF1-Activated Pathways as Potential Next-Generation Anticancer Therapeutics

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2757 ◽  
Author(s):  
Chiranjeev Sharma ◽  
Young Seo
Keyword(s):  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Chemotherapeutic Agents ◽  
Heat Shock Factor 1 ◽  
Next Generation ◽  
Anticancer Activities ◽  
Cancer Cell Growth ◽  
Survival Studies ◽  
New Chemotherapeutic Agents

Targeted therapy is an emerging paradigm in the development of next-generation anticancer drugs. Heat shock factor 1 (HSF1) has been identified as a promising drug target because it regulates several pathways responsible for cancer cell growth, metastasis, and survival. Studies have clearly demonstrated that HSF1 is an effective drug target. Herein, we provide a concise yet comprehensive and integrated overview of progress in developing small molecule inhibitors of HSF1 as next-generation anticancer chemotherapeutics while critically evaluating their potential and challenges. We believe that this review will provide a better understanding of important concepts helpful for outlining the strategy to develop new chemotherapeutic agents with promising anticancer activities by targeting HSF1.

scholarly journals Small Molecule Inhibitors of Influenza Virus Entry

2021 ◽  
Vol 14 (6) ◽  
pp. 587
Author(s):  
Zhaoyu Chen ◽  
Qinghua Cui ◽  
Michael Caffrey ◽  
Lijun Rong ◽  
Ruikun Du
Keyword(s):  
Influenza Virus ◽  
Membrane Fusion ◽  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Virus Entry ◽  
Critical Role ◽  
Structural Basis ◽  
Future Directions ◽  
The Past

Hemagglutinin (HA) plays a critical role during influenza virus receptor binding and subsequent membrane fusion process, thus HA has become a promising drug target. For the past several decades, we and other researchers have discovered a series of HA inhibitors mainly targeting its fusion machinery. In this review, we summarize the advances in HA-targeted development of small molecule inhibitors. Moreover, we discuss the structural basis and mode of action of these inhibitors, and speculate upon future directions toward more potent inhibitors of membrane fusion and potential anti-influenza drugs.

scholarly journals KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics

2018 ◽  
Vol 115 (20) ◽  
pp. E4613-E4622 ◽  
Author(s):  
Bojan Milic ◽  
Anirban Chakraborty ◽  
Kyuho Han ◽  
Michael C. Bassik ◽  
Steven M. Block
Keyword(s):  
Cancer Cell ◽  
Small Molecule ◽  
Single Molecule ◽  
Small Molecule Inhibitors ◽  
Cancer Cell Growth ◽  
Combination Drug ◽  
Cancer Chemotherapeutics ◽  
Development Of Resistance ◽  
Molecule Inhibitor ◽  
Mechanochemical Cycle

Eg5, a mitotic kinesin, has been a target for anticancer drug development. Clinical trials of small-molecule inhibitors of Eg5 have been stymied by the development of resistance, attributable to mitotic rescue by a different endogenous kinesin, KIF15. Compared with Eg5, relatively little is known about the properties of the KIF15 motor. Here, we employed single-molecule optical-trapping techniques to define the KIF15 mechanochemical cycle. We also studied the inhibitory effects of KIF15-IN-1, an uncharacterized, commercially available, small-molecule inhibitor, on KIF15 motility. To explore the complementary behaviors of KIF15 and Eg5, we also scored the effects of small-molecule inhibitors on admixtures of both motors, using both a microtubule (MT)-gliding assay and an assay for cancer cell viability. We found that (i) KIF15 motility differs significantly from Eg5; (ii) KIF15-IN-1 is a potent inhibitor of KIF15 motility; (iii) MT gliding powered by KIF15 and Eg5 only ceases when both motors are inhibited; and (iv) pairing KIF15-IN-1 with Eg5 inhibitors synergistically reduces cancer cell growth. Taken together, our results lend support to the notion that a combination drug therapy employing both inhibitors may be a viable strategy for overcoming chemotherapeutic resistance.

scholarly journals A Primary Evaluation of Potential Small‐Molecule Inhibitors of the Astacin Metalloproteinase Ovastacin, a Novel Drug Target in Female Infertility Treatment

ChemMedChem ◽  
2020 ◽  
Vol 15 (16) ◽  
pp. 1499-1504 ◽  
Author(s):  
Hagen Körschgen ◽  
Christian Jäger ◽  
Kathrin Tan ◽  
Mirko Buchholz ◽  
Walter Stöcker ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Infertility Treatment ◽  
Female Infertility ◽  
Primary Evaluation ◽  
Novel Drug

Identification and Characterization of Novel Small-Molecule Inhibitors of the Replication Checkpoint.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 763-763
Author(s):  
James Bradner ◽  
Yong-Son Kim ◽  
Angela Koehler ◽  
Masaoki Kawasumi ◽  
Xiaodong Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Small Molecule ◽  
Mammalian Cells ◽  
Small Molecule Inhibitors ◽  
Chromatin Condensation ◽  
Replication Stress ◽  
Chemotherapeutic Agents ◽  
Replication Checkpoint ◽  
Chromosomal Fragility ◽  
Microarray Format

Abstract Background The replication (G2/M) checkpoint is principally mediated by the serine/threonine protein kinase ATR (ataxia telangiectasia mutated and Rad3-related). ATR is a large (350 kD) member of the phosphatidylinositol kinase related kinase family. After exposure to genotoxic or replication stress, ATR halts cell cycle progression, allowing DNA repair complexes time enough to restore the fidelity of the genome prior to cell division. Previous experiments have demonstrated that cancer cells with p53 mutation are critically dependent on ATR-mediated arrest of the cell cycle. Industrial approaches to identify ATR inhibitors have failed likely as a result of protein insolubility. Methods We have undertaken a novel chemical genetic approach employing small molecule microarrays (SMMs) to identify molecules with high binding specificity for ATR. Three diversity-oriented combinatorial chemical libraries of more than 15,000 entities were generated by split-pool synthesis in solid phase on polystyrene macrobead supports. Compounds were robotically printed in microarray format on glass slides. Four analogs of FK506 were printed as positive controls. Extracts were prepared from mammalian cells transfected with over-expression constructs of FLAG-tagged ATR, FKBP12 and GFP. A protocol was developed and optimized for screening employing a primary anti-FLAG mouse monoclonal antibody and Cy5-fluorophore labeled anti-mouse antibody. Data analysis for small molecule binders was performed with GenePix software on an Axon Scanner. Biological activity of these molecules was analyzed in the context of mitotic spread and chromosomal fragility assays. Results Protein expression and antibody fidelity was verified by Western blot. The lysate-based SMM screening approach was optimized and validated by recognition of an interaction between over-expressed, epitope-tagged FKBP12 and analogs of FK506. Six small molecule hits suggesting ATR binding were identified and verified by triplicate microarray assays. Positive compounds were structurally similar members of a dihydropyrancarboxamide library suggesting recognition of a common target. Mitotic spread analysis of cells treated with two of these molecules and hydroxyurea demonstrated the premature chromatin condensation phenotype characteristic of replication checkpoint inhibition. Chromosomal fragility was notably augmented by these molecules as well. Chemosensitivity following replication stress was witnessed in p53-negative cells relative to an otherwise identical wild-type cell line. Conclusions Classical approaches to drug discovery are often limited by challenges in protein biochemistry such as protein size, solubility, activity and yield. We present compelling data that the small molecule microarray format can effectively be tailored for use with cellular lysates over-expressing a protein target of biological interest. Furthermore, we have used an optimized protocol to identify two novel, active small molecule inhibitors of the replication checkpoint (SMIRC-1 and SMIRC-2). The enhanced chemosensitivity in p53-negative cell lines supports a plausible role for ATR inhibitors as potentially useful chemotherapeutic agents.

scholarly journals BRCA1 as a Therapeutic Target in Sporadic Epithelial Ovarian Cancer

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Katherine V. Clark-Knowles ◽  
Anna M. O'Brien ◽  
Johanne I. Weberpals
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Chemotherapeutic Agents ◽  
Brca1 Protein ◽  
Critical Pathways ◽  
Promising Target ◽  
Increased Sensitivity ◽  
Preclinical And Clinical Studies

In sporadic epithelial ovarian cancer (EOC), the inactivation of BRCA1 through various mechanisms is a relatively common event. BRCA1 protein dysfunction results in the breakdown of various critical pathways in the cell, notably, the DNA damage response and repair pathway. Tumors from patients withBRCA1germline mutations have an increased sensitivity to DNA damaging chemotherapeutic agents, such as cisplatin, due to defective DNA repair. Thus, inhibiting BRCA1 in sporadic EOC using novel targeted therapies is an attractive strategy for the treatment of advanced or recurrent EOC. Several classes of small molecule inhibitors that affect BRCA1 have now been tested in preclinical and clinical studies suggesting that this is a rational therapeutic approach. The aim of this paper is to provide an understanding of how BRCA1 has evolved into a promising target for the treatment of sporadic disease and to outline the main potential small molecule inhibitors of BRCA1 in EOC.

Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth

2006 ◽  
Vol 5 (4) ◽  
pp. 1079-1086 ◽  
Author(s):  
Karissa L. Gable ◽  
Betty A. Maddux ◽  
Cristina Penaranda ◽  
Marianna Zavodovskaya ◽  
Michael J. Campbell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cell Growth ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Cancer Cell Growth ◽  
Breast Cancer Cell Growth ◽  
Factor I

scholarly journals Allosteric Targeting of Aurora A Kinase Using Small Molecules: A Step Forward Towards Next Generation Medicines?

2019 ◽  
Vol 26 (13) ◽  
pp. 2234-2242 ◽  
Author(s):  
Resmi C. Panicker ◽  
Anthony G. Coyne ◽  
Rajavel Srinivasan
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Research Work ◽  
Surface Enhanced Raman Spectroscopy ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Next Generation ◽  
Allosteric Site ◽  
Site Binding

Background: Aurora A (AurA) kinase is a key mitotic protein implicated in cancer. Several small molecule inhibitors targeting the ATP binding site of this enzyme are in various stages of clinical development. However, these inhibitors can result in selectivity and drug resistance problems. Allosteric inhibition of kinases using small molecules is an alternative strategy to target these enzymes selectively and these could serve as the seeds for next generation medicines. This review discusses the developments in the non-ATP site binding small molecule inhibitors of AurA and their prospect as future therapeutics. Discussion: Allosteric targeting of AurA kinase using small molecules is relatively a new strategy, and only a handful of research work has been reported. Two patents and three papers pertaining to allosteric targeting of AurA kinase using small molecules were covered in this review. Topics discussed include, identification of small molecule inhibitors targeting AurA- Targeting Protein for Xenopus kinesin-like protein 2 (TPX2) interaction, anacardic acid - a natural product ligand that selectively modulates AurA activity in the presence of Aurora B kinase, and identification of felodipine as an uncompetitive inhibitor of AurA using Surface Enhanced Raman Spectroscopy (SERS) technique Conclusion: Allosteric targeting of therapeutically relevant enzymes using small molecules is a burgeoning research area. New techniques such as fragment-based ligand discovery, SERS methods, etc., are expanding to identify the allosteric site binding ligands. Research in this area is expected to deliver fruitful outcome in terms of novel therapeutics against AurA kinase as well as other therapeutically relevant enzymes.

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