An analysis of growth patterns of targeted therapies (TTs) using keywords from ASCO annual meeting abstracts.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18084-e18084
Author(s):  
Yutao Gong ◽  
Julie A Schneider ◽  
Gideon Michael Blumenthal
Keyword(s):  
Proteasome Inhibitors ◽  
Drug Combinations ◽  
Growth Patterns ◽  
Development Programs ◽  
Target Drug ◽  
Group 4 ◽  
Future Drug ◽  
Median Date ◽  
Asco Meeting ◽  
Future Work

e18084 Background: The number of TTs approved to treat cancer patients has increased dramatically in the past decades. We analyzed how frequently 27 oncology targets (and associated therapies) appeared in ASCO meeting abstracts since 2005 to explore if future drug development patterns could be predicted. Methods: We obtained abstracts from the ASCO Center for Research & Analytics. We used keyword abstraction to calculate the percentage of abstracts referencing 27 specific target/drug combinations each year, and we categorized them into high (HV), medium (MV), and low volume (LV) groups based on percentage in 2018. Results: Table shows data since 2012 for the HV group. The percentages of MV (BCR/ABL, CDK4/6, CD20, MEK, CTLA4, iMID, PARP, PI3K, proteasome inhibitors) and LV (BCL2, BTK, CD19, CD30, CD38, HDAC, IDH1, IDH2, and NTRK) in 2018 were less than 1.7%. The HV group was associated with more FDA-approved therapies (41) than the MV (23) and LV (13) groups. The HV and MV groups are likely enriched for more mature targets, as the median date of relevant drug approvals is earlier (11/2012 and 4/2013, respectively) than the LV group (4/2016). Growth patterns are consistent with key regulatory milestones. The number of abstracts with PD-1/PD-L1-related keywords has grown more rapidly than any other drug/target combination. This growth begins soon before FDA approvals for a diversity of relevant indications. Continued growth likely reflects ongoing clinical trials of several other PD-1/PD-L1 inhibitors and combinations. We identified similar growth trends for other targets just prior to key regulatory approvals. Conclusions: Our analysis revealed interesting growth patterns for key oncology target/drug combinations. Future work will explore whether we can extend the analysis to help predict the evolution of development programs for new targets. [Table: see text]

scholarly journals Chemical Patterns of Proteasome Inhibitors: Lessons Learned from Two Decades of Drug Design

2019 ◽  
Vol 20 (21) ◽  
pp. 5326 ◽  
Author(s):  
Guedes ◽  
Aniceto ◽  
Andrade ◽  
Salvador ◽  
Guedes
Keyword(s):  
Drug Discovery ◽  
Chemical Space ◽  
Decision Rules ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Lessons Learned ◽  
Drug Candidates ◽  
Making Sense ◽  
Structure Activity ◽  
Future Drug

Drug discovery now faces a new challenge, where the availability of experimental data is no longer the limiting step, and instead, making sense of the data has gained a new level of importance, propelled by the extensive incorporation of cheminformatics and bioinformatics methodologies into the drug discovery and development pipeline. These enable, for example, the inference of structure-activity relationships that can be useful in the discovery of new drug candidates. One of the therapeutic applications that could benefit from this type of data mining is proteasome inhibition, given that multiple compounds have been designed and tested for the last 20 years, and this collection of data is yet to be subjected to such type of assessment. This study presents a retrospective overview of two decades of proteasome inhibitors development (680 compounds), in order to gather what could be learned from them and apply this knowledge to any future drug discovery on this subject. Our analysis focused on how different chemical descriptors coupled with statistical tools can be used to extract interesting patterns of activity. Multiple instances of the structure-activity relationship were observed in this dataset, either for isolated molecular descriptors (e.g., molecular refractivity and topological polar surface area) as well as scaffold similarity or chemical space overlap. Building a decision tree allowed the identification of two meaningful decision rules that describe the chemical parameters associated with high activity. Additionally, a characterization of the prevalence of key functional groups gives insight into global patterns followed in drug discovery projects, and highlights some systematically underexplored parts of the chemical space. The various chemical patterns identified provided useful insight that can be applied in future drug discovery projects, and give an overview of what has been done so far.

scholarly journals Effects of Elevated Ambient Temperature on Reproductive Outcomes and Offspring Growth Depend on Exposure Time

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Huda Yahia Hamid ◽  
Md Zuki Abu Bakar Zakaria ◽  
Goh Yong Meng ◽  
Abd. Wahid Haron ◽  
Noordin Mohamed Mustapha
Keyword(s):  
Elevated Temperature ◽  
Ambient Temperature ◽  
Sex Ratios ◽  
Growth Patterns ◽  
Gestation Length ◽  
Reproductive Outcomes ◽  
Group 4 ◽  
Offspring Growth ◽  
Group 3 ◽  
Group 1

Reproductive performance has been shown to be greatly affected by changes in environmental factors, such as temperature. However, it is also crucial to identify the particular stage of pregnancy that is most adversely affected by elevated ambient temperature. The aims of this study were to determine the effect on reproductive outcomes of exposure to elevated ambient temperature during different stages of pregnancy and to determine the effect of prenatal heat stress on offspring growth. Sixty pregnant rats were used in this study. The rats were divided equally into four groups as group 1 (control), group 2 (exposed to elevated temperature following implantation), group 3 (exposed to elevated temperature during pre- and periimplantation), and group 4 (exposed to elevated temperature during pre- and periimplantation and following implantation). Groups 3 and 4 had prolonged gestation periods, reduced litter sizes, and male-biased sex ratios. Moreover, the growth patterns of group 3 and 4 pups were adversely affected by prenatal exposure to elevated temperature. The differences between group 1 and group 3 and between group 1 and group 4 were highly significant. However, no significant differences were observed between groups 1 and 2 in the gestation length, sex ratios, and growth patterns. Thus, it can be concluded that exposure to elevated ambient temperature during pre- and periimplantation has stronger adverse effects on reproductive outcomes and offspring growth than postimplantation exposure.

Practical Considerations for Antibodies in Myeloma

2018 ◽  
pp. 667-674 ◽  
Author(s):  
Jacob P. Laubach ◽  
Niels van de Donk ◽  
Faith E. Davies ◽  
Joseph Mikhael
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Patient Outcomes ◽  
Great Improvement ◽  
Treatment Options ◽  
Proteasome Inhibitors ◽  
Drug Combinations ◽  
Therapeutic Antibodies ◽  
Immunomodulatory Drugs ◽  
Favorable Safety

The development of the monoclonal antibodies daratumumab and elotuzumab has expanded treatment options for multiple myeloma and led to great improvement in patient outcomes. These agents have favorable safety profiles and synergize effectively with established agents used in the management of myeloma, namely immunomodulatory drugs and proteasome inhibitors. This article reviews the rationale for use of monoclonal antibodies in myeloma, current approved indications for daratumumab and elotuzumab, the manner in which these agents are used in the overall management of myeloma, and specific challenges associated with their use in the clinic. It also highlights other, emerging drug combinations that incorporate daratumumab or elotuzumab and profiles new therapeutic antibodies currently under development.

scholarly journals From Low-Dose Fixed Combinations for Arterial Hypertension Treatment to Multi-Target Therapy of Cardiovascular Diseases

2020 ◽  
Vol 16 (4) ◽  
pp. 638-643
Author(s):  
P. A. Lebedev ◽  
A. A. Garanin
Keyword(s):  
Cardiovascular Diseases ◽  
Arterial Hypertension ◽  
Target Therapy ◽  
Drug Combinations ◽  
Evolutionary Development ◽  
Social Significance ◽  
Therapeutic Goals ◽  
Target Drug ◽  
Risk Patients ◽  
Cardiovascular Continuum

The article presents the evolutionary development of combination therapy from the creation of a multicomponent tablet for the treatment of arterial hypertension (AH) to modern multi-target fixed combinations as the most effective approach to the fight against cardiovascular diseases (CVD). The priority of domestic scientists, in particular academician A.L. Myasnikov, in the development and creation of a combined drug for AH treatment is shown. The development of pharmacology and pharmaceutical technologies has allowed to expand the range of possible drug combinations for AH therapy, and the discovery of new pathophysiological mechanisms involved in the cardiovascular continuum has led to the understanding of the close links between AH and atherosclerosis. This fact prompted the scientific community to search for and implement in practice drug combinations that would allow multi-target therapy, that is, to influence several pathological processes and achieve a number of therapeutic goals. The presented review testifies to the transformation of the concept of fixed combinations for patients with AH into the concept of a multi-target drug. Multi-targeting is achieved not only by the pleotropic of components known as hypotensive agents, but also by combination with statins. Taking into account the wide AH prevalence in the population, its high medical and social significance, the critical importance as a risk factor for CVD, the authors consider a justified clinical and epidemiological approach to primary prevention of CVD with the widespread use of multi-targeted therapy in all high-risk patients with AH. It is expedient to develop new domestic medicines that implement the concept of a multi-targeted drug, to include them in the list of vital medicines, to increase the availability of these drugs to the population on the basis of preferential programs.

Drug Combinations with Proteasome Inhibitors in Antitumor Therapy

2013 ◽  
Vol 19 (22) ◽  
pp. 4094-4114 ◽  
Author(s):  
Laura Gatti ◽  
Valentina Zuco ◽  
Nadia Zaffaroni ◽  
Paola Perego
Keyword(s):  
Proteasome Inhibitors ◽  
Drug Combinations ◽  
Antitumor Therapy

scholarly journals DrugComb: an integrative cancer drug combination data portal

2019 ◽  
Vol 47 (W1) ◽  
pp. W43-W51 ◽  
Author(s):  
Bulat Zagidullin ◽  
Jehad Aldahdooh ◽  
Shuyu Zheng ◽  
Wenyu Wang ◽  
Yinyin Wang ◽  
...  
Keyword(s):  
Drug Combination ◽  
Drug Combinations ◽  
Cancer Drug ◽  
Data Repository ◽  
High Throughput Drug Screening ◽  
Chemical Fingerprints ◽  
Level Data ◽  
Future Drug ◽  
Data Portal ◽  
Informatics Tools

AbstractDrug combination therapy has the potential to enhance efficacy, reduce dose-dependent toxicity and prevent the emergence of drug resistance. However, discovery of synergistic and effective drug combinations has been a laborious and often serendipitous process. In recent years, identification of combination therapies has been accelerated due to the advances in high-throughput drug screening, but informatics approaches for systems-level data management and analysis are needed. To contribute toward this goal, we created an open-access data portal called DrugComb (https://drugcomb.fimm.fi) where the results of drug combination screening studies are accumulated, standardized and harmonized. Through the data portal, we provided a web server to analyze and visualize users’ own drug combination screening data. The users can also effectively participate a crowdsourcing data curation effect by depositing their data at DrugComb. To initiate the data repository, we collected 437 932 drug combinations tested on a variety of cancer cell lines. We showed that linear regression approaches, when considering chemical fingerprints as predictors, have the potential to achieve high accuracy of predicting the sensitivity of drug combinations. All the data and informatics tools are freely available in DrugComb to enable a more efficient utilization of data resources for future drug combination discovery.

scholarly journals DrugComb - an integrative cancer drug combination data portal

2019 ◽  
Author(s):  
Bulat Zagidullin ◽  
Jehad Aldahdooh ◽  
Shuyu Zheng ◽  
Wenyu Wang ◽  
Yinyin Wang ◽  
...  
Keyword(s):  
Drug Combination ◽  
Drug Combinations ◽  
Cancer Drug ◽  
Data Repository ◽  
High Throughput Drug Screening ◽  
Chemical Fingerprints ◽  
Level Data ◽  
Future Drug ◽  
Data Portal ◽  
Informatics Tools

ABSTRACTDrug combination therapy has the potential to enhance efficacy, reduce dose-dependent toxicity and prevent the emergence of drug resistance. However, discovery of synergistic and effective drug combinations has been a laborious and often serendipitous process. In recent years, identification of combination therapies has been accelerated due to the advances in high-throughput drug screening, but informatics approaches for systems-level data management and analysis are needed. To contribute toward this goal, we created an open-access data portal (https://drugcomb.fimm.fi) where the results of drug combination screening studies are accumulated, standardized and harmonized. Through the data portal, we provided the web server to analyze and visualize users’ own drug combination screening data. The users have an option to upload their data to DrugComb, as part of a crowdsourcing data curation effort. To initiate the data repository, we collected 437,932 drug combinations tested on a variety of cancer cell lines. We showed that linear regression approaches, when considering chemical fingerprints as predictors, have the potential to achieve high accuracy of predicting the sensitivity and synergy of drug combinations. All the data and informatics tools are freely available in DrugComb to enable a more efficient utilization of data resources for future drug combination discovery.

scholarly journals Natural Products from Actinobacteria Associated with Fungus-Growing Termites

Antibiotics ◽  
2018 ◽  
Vol 7 (3) ◽  
pp. 83 ◽  
Author(s):  
René Benndorf ◽  
Huijuan Guo ◽  
Elisabeth Sommerwerk ◽  
Christiane Weigel ◽  
Maria Garcia-Altares ◽  
...  
Keyword(s):  
Natural Products ◽  
Chemical Analysis ◽  
Natural Product ◽  
Culture Broth ◽  
Insect Host ◽  
Development Programs ◽  
Fungus Garden ◽  
The Past ◽  
Future Drug ◽  
Axenic Strains

The chemical analysis of insect-associated Actinobacteria has attracted the interest of natural product chemists in the past years as bacterial-produced metabolites are sought to be crucial for sustaining and protecting the insect host. The objective of our study was to evaluate the phylogeny and bioprospecting of Actinobacteria associated with fungus-growing termites. We characterized 97 Actinobacteria from the gut, exoskeleton, and fungus garden (comb) of the fungus-growing termite Macrotermes natalensis and used two different bioassays to assess their general antimicrobial activity. We selected two strains for chemical analysis and investigated the culture broth of the axenic strains and fungus-actinobacterium co-cultures. From these studies, we identified the previously-reported PKS-derived barceloneic acid A and the PKS-derived rubterolones. Analysis of culture broth yielded a new dichlorinated diketopiperazine derivative and two new tetracyclic lanthipeptides, named rubrominins A and B. The discussed natural products highlight that insect-associated Actinobacteria are highly prolific natural product producers yielding important chemical scaffolds urgently needed for future drug development programs.

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