Recent Trends in rationally designed molecules as kinase inhibitors

2021 ◽  
Vol 28 ◽  
Author(s):  
Parteek Prasher ◽  
Mousmee Sharma ◽  
Yinghan Chan ◽  
Sachin Kumar Singh ◽  
Krishnan Anand ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Cancer Targeting ◽  
Physiological Processes ◽  
Cancer Pathogenesis ◽  
Emerging Trends ◽  
Inhibition Of Angiogenesis ◽  
Recent Trends ◽  
And Function ◽  
Phosphate Groups

: Protein kinases modulate the structure and function of proteins by adding phosphate groups to threonine, tyrosine, and serine residues. The phosphorylation process mediated by the kinases regulates several physiological processes, while their overexpression results in the development of chronic diseases, including cancer. Targeting of receptor tyrosine kinase pathways results in the inhibition of angiogenesis and cell proliferation that validates kinases as a key target in the management of aggressive cancers. As such, the identification of protein kinase inhibitors revolutionized the contemporary anticancer therapy by inducing a paradigm shift in the management of disease pathogenesis. Contemporary drug design programs focus on a broad range of kinase targets for the development of novel pharmacophores to manage the overexpression of kinases and their pathophysiology in cancer pathogenesis. In this review, we present the emerging trends in the development of rationally designed molecular inhibitors of kinases over the last five years (2016-2021) and their incipient role in the development of impending anticancer pharmaceuticals.

FLT3-ITD Signaling Induces Oncogenic Mir-155 by NF-κB and STAT5 Pathways In Acute Myeloid Leukemia Thereby Targeting Transcription Factor PU.1,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3469-3469
Author(s):  
Dennis Gerloff ◽  
Daniela Braeuer-Hartmann ◽  
Christiane Katzerke ◽  
Jens-Uwe Hartmann ◽  
Carsten Mueller-Tidow ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
In Silico Analysis ◽  
Protein Kinase Inhibitors ◽  
U937 Cells ◽  
Differentiation Block ◽  
And Function ◽  
Acute Myeloid

Abstract Abstract 3469 Almost 30% of all acute myeloid leukemias (AML) are associated with an internal tandem duplication (ITD) in the juxtamembrane of FLT3. This mutation leads to constitutively activated FLT3 signaling, which also includes altered FLT3 targets like STAT5. The dysregulation of pathways causes a differentiation block and plays a role in inhibition of hematopoietic transcription factors like PU.1 and C/EBPalpha. Here we report that FLT3-ITD signaling induces the oncogenic miR-155 by NF-κB and STAT5 pathways. Furthermore we demonstrate that miR-155 targets the myeloid transcription factor PU.1. Analysis of FLT3-ITD positive patient samples show an approximately 2 fold higher miR-155 expression compared to FLT3-WT associated AMLs. Besides, the overexpression of FLT3-ITD in myeloid U937 cells increases miR-155 expression 2,2 fold. In contrast, a block of FLT3-ITD signalling in FLT3-ITD associated cell line MV4;11 by protein kinase inhibitors (PKIs), PKC412, SU5614 and CEP701, results in an 80% decreased miR-155 expression. In further experiments we analyzed the role of FLT3-ITD downstream targets NF-κB (p65) and STAT5 in miR-155 regulation. We show that siRNA mediated knockdown of NF-κB (p65) or STAT5 in MV4;11 cells correlates with reduced miR-155 expression. In addition we demonstrate that p65 binds to the miR-155 promoter in MV4;11 cells while the treatment with the PKI CEP701 results in a p65 release from the miR-155 promoter. Furthermore, we prove that miR-155 overexpression in PMA (phorbol 12-myristate 13-acetate) treated U937 cells reduces macrophage differentiation about 50%. In in silico analysis we found PU.1 as a putative miR-155 target. Interestingly, we could show that overexpression of FLT3-ITD and miR-155 reduces the PU.1 protein level in U937 cells, respectively. These data elucidate the regulation and function of miR-155 in FLT3-ITD associated AML and may lead to a better understanding of the role of miRNAs in leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

Matrix Metalloproteinases in Invertebrates

2020 ◽  
Vol 27 (11) ◽  
pp. 1068-1081
Author(s):  
Xi Liu ◽  
Dongwu Liu ◽  
Yangyang Shen ◽  
Mujie Huang ◽  
Lili Gao ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Immune Responses ◽  
Theoretical Basis ◽  
Regulatory Mechanism ◽  
Structure And Function ◽  
Catalytic Domains ◽  
Physiological Processes ◽  
Disease Occurrence ◽  
Complex Functions ◽  
And Function

Matrix Metalloproteinases (MMPs) belong to a family of metal-dependent endopeptidases which contain a series of conserved pro-peptide domains and catalytic domains. MMPs have been widely found in plants, animals, and microorganisms. MMPs are involved in regulating numerous physiological processes, pathological processes, and immune responses. In addition, MMPs play a key role in disease occurrence, including tumors, cardiovascular diseases, and other diseases. Compared with invertebrate MMPs, vertebrate MMPs have diverse subtypes and complex functions. Therefore, it is difficult to study the function of MMPs in vertebrates. However, it is relatively easy to study invertebrate MMPs because there are fewer subtypes of MMPs in invertebrates. In the present review, the structure and function of MMPs in invertebrates were summarized, which will provide a theoretical basis for investigating the regulatory mechanism of MMPs in invertebrates.

Extracellular Vesicles in Tumor Diagnosis: A Mini-Review

2020 ◽  
Vol 20 ◽  
Author(s):  
Si Yu ◽  
Menglin Huang ◽  
Jingyu Wang ◽  
Yongchang Zheng ◽  
Haifeng Xu
Keyword(s):  
Clinical Diagnosis ◽  
Sensitivity And Specificity ◽  
Cancer Diagnosis ◽  
Cancer Biomarkers ◽  
Related Substances ◽  
Physiological Processes ◽  
Cancer Pathogenesis ◽  
Limited Application ◽  
Low Sensitivity ◽  
Shed Light

: Widely exploration of noninvasive tumor/cancer biomarkers has shed light on clinical diagnosis. However, many under-investigated biomarkers showed limited application potency due to low sensitivity and specificity, while extracellular vehicles (EVs) were gradually recognized as promising candidates. EVs are small vesicles transporting bioactive cargos between cells in multiple physiological processes and also in tumor/cancer pathogenesis. This review aimed to offer recent studies of EVs on structure, classification, physiological functions, as well as changes in tumor initiation and progression. Furthermore, we focused on advances of EVs and/or EV-related substances in cancer diagnosis, and summarized ongoing studies of promising candidates for future investigations.

Alkaloids as Anticancer Agents: A Review of Chinese Patents in Recent 5 Years

2020 ◽  
Vol 15 (1) ◽  
pp. 2-13 ◽  
Author(s):  
Hongyu Tao ◽  
Ling Zuo ◽  
Huanli Xu ◽  
Cong Li ◽  
Gan Qiao ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Cdk Inhibitors ◽  
Comprehensive Overview ◽  
P53 Expression ◽  
Study Results

Background: In recent years, many novel alkaloids with anticancer activity have been found in China, and some of them are promising for developing as anticancer agents. Objective: This review aims to provide a comprehensive overview of the information about alkaloid anticancer agents disclosed in Chinese patents, and discusses their potential to be developed as anticancer drugs used clinically. Methods: Anticancer alkaloids disclosed in Chinese patents in recent 5 years were presented according to their mode of actions. Their study results published on PubMed, and SciDirect databases were presented. Results: More than one hundred anticancer alkaloids were disclosed in Chinese patents and their mode of action referred to arresting cell cycle, inhibiting protein kinases, affecting DNA synthesis and p53 expression, etc. Conclusion: Many newly found alkaloids displayed potent anticancer activity both in vitro and in vivo, and some of the anticancer alkaloids acted as protein kinase inhibitors or CDK inhibitors possess the potential for developing as novel anticancer agents.

scholarly journals Overview on the Different Patterns of Tumor Vascularization

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 639
Author(s):  
Domenico Ribatti ◽  
Francesco Pezzella
Keyword(s):  
Vasculogenic Mimicry ◽  
Endothelial Cell Proliferation ◽  
Published Data ◽  
Alternative Mechanism ◽  
Tumor Vascularization ◽  
Angiogenic Therapy ◽  
Physiological Processes ◽  
Inhibition Of Angiogenesis ◽  
Therapeutic Development

Angiogenesis is a crucial event in the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads to the formation of a vascular network of tumor-associated capillaries promoting survival and proliferation of the tumor cells. Starting with the hypothesis formulated by Judah Folkman that tumor growth is angiogenesis-dependent, this area of research has a solid scientific foundation and inhibition of angiogenesis is a major area of therapeutic development for the treatment of cancer. Over this period numerous authors published data of vascularization of tumors, which attributed the cause of neo-vascularization to various factors including inflammation, release of angiogenic cytokines, vasodilatation, and increased tumor metabolism. More recently, it has been demonstrated that tumor vasculature is not necessarily derived by endothelial cell proliferation and sprouting of new capillaries, but alternative vascularization mechanisms have been described, namely vascular co-option and vasculogenic mimicry. In this article, we have analyzed the mechanisms involved in tumor vascularization in association with classical angiogenesis, including post-natal vasculogenesis, intussusceptive microvascular growth, vascular co-option, and vasculogenic mimicry. We have also discussed the role of these alternative mechanism in resistance to anti-angiogenic therapy and potential therapeutic approaches to overcome resistance.

scholarly journals Histone deacetylase (HDAC) 9: versatile biological functions and emerging roles in human cancer

2021 ◽  
Author(s):  
Chun Yang ◽  
Stéphane Croteau ◽  
Pierre Hardy
Keyword(s):  
Histone Deacetylase ◽  
Posttranslational Modifications ◽  
Histone Deacetylases ◽  
Muscle Development ◽  
Target Genes ◽  
Human Cancer ◽  
Expression Patterns ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Pathogenesis

Abstract Background HDAC9 (histone deacetylase 9) belongs to the class IIa family of histone deacetylases. This enzyme can shuttle freely between the nucleus and cytoplasm and promotes tissue-specific transcriptional regulation by interacting with histone and non-histone substrates. HDAC9 plays an essential role in diverse physiological processes including cardiac muscle development, bone formation, adipocyte differentiation and innate immunity. HDAC9 inhibition or activation is therefore a promising avenue for therapeutic intervention in several diseases. HDAC9 overexpression is also common in cancer cells, where HDAC9 alters the expression and activity of numerous relevant proteins involved in carcinogenesis. Conclusions This review summarizes the most recent discoveries regarding HDAC9 as a crucial regulator of specific physiological systems and, more importantly, highlights the diverse spectrum of HDAC9-mediated posttranslational modifications and their contributions to cancer pathogenesis. HDAC9 is a potential novel therapeutic target, and the restoration of aberrant expression patterns observed among HDAC9 target genes and their related signaling pathways may provide opportunities to the design of novel anticancer therapeutic strategies.

scholarly journals Thiazolidine-diones. Biochemical and biological activity of a novel class of tyrosine protein kinase inhibitors.

1990 ◽  
Vol 265 (36) ◽  
pp. 22255-22261
Author(s):  
J F Geissler ◽  
P Traxler ◽  
U Regenass ◽  
B J Murray ◽  
J L Roesel ◽  
...  
Keyword(s):  
Biological Activity ◽  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Tyrosine Protein Kinase
Sign in / Sign up

Export Citation Format

Share Document