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Journal ArticleDOI: 10.1021/ACS.JMEDCHEM.0C01180

Small-Molecule Drug Discovery in Triple Negative Breast Cancer: Current Situation and Future Directions.

02 Mar 2021-Journal of Medicinal Chemistry (American Chemical Society (ACS))-Vol. 64, Iss: 5, pp 2382-2418
Abstract: Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, but an effective targeted therapy has not been well-established so far. Considering the lack of effective targets, where do we go next in the current TNBC drug development? A promising intervention for TNBC might lie in de novo small-molecule drugs that precisely target different molecular characteristics of TNBC. However, an ideal single-target drug discovery still faces a huge challenge. Alternatively, other new emerging strategies, such as dual-target drug, drug repurposing, and combination strategies, may provide new insight into the improvement of TNBC therapeutics. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in TNBC therapy, including single-target drugs, dual-target drugs, as well as drug repurposing and combination strategies that will together shed new light on the future directions targeting TNBC vulnerabilities with small-molecule drugs for future therapeutic purposes.

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Topics: Drug development (55%), Drug repositioning (51%)

6 results found

Journal ArticleDOI: 10.1016/J.EJMECH.2021.113424
Tian Xu1, Jifa Zhang1, Chengcan Yang1, Ryszard Pluta2  +4 moreInstitutions (3)
Abstract: Triple negative breast cancer (TNBC) has a worse prognosis than other types of breast cancer due to its special biological behavior and clinicopathological characteristics. TNBC cell proliferation and progression to metastasis can be suppressed by inducing cytostatic autophagy. mTOR is closely related to autophagy and is involved in protein synthesis, nutrient metabolism and activating mTOR promotes tumor growth and metastasis. In this paper, we adopted the strategy of structure simplification, aimed to look for novel small-molecule inhibitors of mTOR by pharmacophore-based virtual screening and biological activity determination. We found a lead compound with 3-bromo-N’-(4-hydroxybenzylidene)-4-methylbenzohydrazide for rational drug design and structural modification, then studied its structure-activity relationship. After that, compound 7c with the best TNBC cells inhibitory activities and superior mTOR enzyme inhibitory activity was obtained. In addition, we found that compound 7c could induce autophagic cell death and apoptosis in MDA-MB-231 and MDA-MB-468 cell lines. In conclusion, these findings provide new clues for our 3-bromo-N’-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives, which are expected to become drug candidates for the treatment of TNBC in the future.

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Topics: PI3K/AKT/mTOR pathway (56%), Programmed cell death (54%), Triple-negative breast cancer (52%) ... read more

2 Citations

Journal ArticleDOI: 10.1021/ACS.JMEDCHEM.0C02268
Jin Zhang1, Jin Zhang2, Ling Zou2, Danfeng Shi3  +8 moreInstitutions (4)
Abstract: Sirtuin-3 (SIRT3) is an NAD+-dependent protein deacetylase localized primarily in the mitochondria with many links to different types of human cancers. Autophagy, which is a highly conserved lysosomal degradation process in eukaryotic cells, has been recently reported to be positively regulated by SIRT3 in cancer; therefore, activating SIRT3-modulated autophagy may be a promising strategy for drug discovery. In this study, we discovered a small-molecule activator of SIRT3 compound 33c (ADTL-SA1215) with specific SIRT3 deacetylase activity by structure-guided design and high-throughput screening. Subsequently, compound 33c inhibited the proliferation and migration of human breast carcinoma MDA-MB-231 cells by SIRT3-driven autophagy/mitophagy signaling pathways in vitro and in vivo. Collectively, these results demonstrate that pharmacological activation of SIRT3 is a potential therapeutic approach of triple negative breast cancer (TNBC). More importantly, compound 33c may be a first-in-class specific small-molecule activator of SIRT3 that would be utilized for future cancer drug development.

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Topics: Mitophagy (60%), Deacetylase activity (59%), SIRT3 (57%) ... read more

1 Citations

Open accessPosted ContentDOI: 10.1101/2021.09.06.459060
Shuyun He1, Duancheng Zhao1, Yanle Ling1, Hanxuan Cai1  +3 moreInstitutions (1)
06 Sep 2021-bioRxiv
Abstract: Summary Breast cancer (BC) has surpassed lung cancer as the most frequently occurring cancer, and it is the leading cause of cancer-related death in women. Therefore, there is an urgent need to discover or design new drug candidates for BC treatment. In this study, we first collected a series of structurally diverse datasets consisting of 33,757 active and 21,152 inactive compounds for 13 breast cancer cell lines and one normal breast cell line commonly used in in vitro antiproliferative assays. Predictive models were then developed using five conventional machine learning algorithms, including naive Bayesian, support vector machine, k-Nearest Neighbors, random forest, and extreme gradient boosting, as well as five deep learning algorithms, including deep neural networks, graph convolutional networks, graph attention network, message passing neural networks, and Attentive FP. A total of 476 single models and 112 fusion models were constructed based on three types of molecular representations including molecular descriptors, fingerprints, and graphs. The evaluation results demonstrate that the best model for each BC cell subtype can achieve high predictive accuracy for the test sets with AUC values of 0.689–0.993. Moreover, important structural fragments related to BC cell inhibition were identified and interpreted. To facilitate the use of the model, an online webserver called ChemBC and its local version software were developed to predict potential anti-BC agents. Availability ChemBC webserver is available at and its local version Python software is maintained at a GitHub repository ( Contact or Supplementary information Supplementary data are available at Bioinformatics online.

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Open accessJournal ArticleDOI: 10.1021/ACS.JMEDCHEM.1C01069
Guoshun Luo1, Xin Lin1, Antonio Vega-Medina2, Maoxu Xiao1  +4 moreInstitutions (2)
Abstract: The transcription factor FOXM1 that regulates multiple proliferation-related genes through selective protein-DNA and protein-protein interactions is now considered an attractive oncotarget. There are several small-molecule inhibitors that indirectly suppress the expression of FOXM1 or block its DNA binding domain (FOXM1-DBD). However, insufficient specificity or/and efficacy are two potential drawbacks. Here, we employed in silico modeling of FOXM1-DBD with inhibitors to enable the design of an effective CRBN-recruiting molecule that induced significant FOXM1 protein degradation and exerted promising in vivo antitumor activity against TNBC xenograft models. This study is the first of its kind showcasing the use of an approach described in the literature as protein-targeting chimeras to degrade the elusive FOXM1, providing an alternative strategy to counter the pathological effects resulting from the increased transcriptional activity of FOXM1 observed in cancer cells.

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Topics: Ubiquitin ligase (50%)

Journal ArticleDOI: 10.1021/ACS.JMEDCHEM.1C01350
Dan Wei1, Hanlin Wang2, Hanlin Wang1, Qinghe Zeng1  +14 moreInstitutions (3)
Abstract: Triple-negative breast cancer (TNBC) is highly aggressive with very limited treatment options due to the lack of efficient targeted therapies and thus still remains clinically challenging. Targeting transcription-associated cyclin-dependent kinases to remodel transcriptional regulation shows great promise in cancer therapy. Herein, we report the synthesis, optimization, and evaluation of new series of heterobifunctional molecules as highly selective and efficacious CDK9 degraders, enabling potent inhibition of TNBC cell growth and rapidly targeted degradation of CDK9. Moreover, the most potent CDK9 degrader (compound 45) induces cell apoptosis in vitro and inhibits tumor growth in the MDA-MB-231 TNBC model. Furthermore, the RNA-seq, immunohistochemistry assays demonstrate that the CDK9 degrader downregulates the downstream targets, such as MYC, at the transcriptional level, resulting apoptosis in TNBC cells. Our work establishes that 45 is a highly potent and efficacious CDK9 degrader for targeting transcription regulation, which represents an effective strategy and great potential as a new targeted therapy for TNBC.

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Topics: Targeted therapy (56%)


214 results found

Open accessJournal ArticleDOI: 10.3322/CAAC.21551
Abstract: Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.

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Topics: Cancer Death Rate (71%), Cancer prevention (66%), Mortality rate (60%) ... read more

11,980 Citations

Open accessJournal ArticleDOI: 10.1038/NMETH.3337
01 May 2015-Nature Methods
Abstract: We introduce CIBERSORT, a method for characterizing cell composition of complex tissues from their gene expression profiles When applied to enumeration of hematopoietic subsets in RNA mixtures from fresh, frozen and fixed tissues, including solid tumors, CIBERSORT outperformed other methods with respect to noise, unknown mixture content and closely related cell types CIBERSORT should enable large-scale analysis of RNA mixtures for cellular biomarkers and therapeutic targets (http://cibersortstanfordedu/)

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3,483 Citations

Open accessJournal ArticleDOI: 10.1172/JCI45014
Brian D. Lehmann1, Joshua A. Bauer1, Xi Chen1, Melinda E. Sanders1  +3 moreInstitutions (1)
Abstract: Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted “driver” signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.

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Topics: Triple-negative breast cancer (54%), Triple-Negative Breast Carcinoma (51%), Dasatinib (50%) ... read more

3,481 Citations

Journal ArticleDOI: 10.1016/S0140-6736(10)60893-8
Andrew Tutt1, Mark E. Robson2, Judy Garber3, Susan M. Domchek4  +11 moreInstitutions (12)
24 Jul 2010-The Lancet
Abstract: Summary Background Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA -deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA -deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. Methods Women (aged ≥18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with, number NCT00494234. Findings Patients had been given a median of three previous chemotherapy regimens (range 1–5 in cohort 1, and 2–4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25–59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11–41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). Interpretation The results of this study provide positive proof of concept for PARP inhibition in BRCA -deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1 -associated or BRCA2 -associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations. Funding AstraZeneca.

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Topics: Olaparib (59%), Prospective cohort study (53%), PARP inhibitor (52%) ... read more

1,986 Citations

Open accessJournal ArticleDOI: 10.1056/NEJMOA1706450
Mark E. Robson1, Seock-Ah Im2, Elżbieta Senkus3, Binghe Xu4  +10 moreInstitutions (10)
Abstract: BackgroundOlaparib is an oral poly(adenosine diphosphate–ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation. MethodsWe conducted a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)–negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single-agent chemotherapy of the physician’s choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review and was analyzed on an intention-to-treat basis. ResultsOf the 302 patients who underwent randomization, 205 were assigned to receive...

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Topics: Olaparib (65%), BRCA mutation (60%), Vinorelbine (59%) ... read more

1,270 Citations