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RUXOLITINIB: THE JACK FOR JAK INHIBITION

6823 views | Mar 13 2012

Ruxolitinib: Inhibition of the Janus Kinases The janus kinases are a sub family of the protein kinases and are refer to as non receptor tyrosine kinases. Signals from the Janus kinases regulate several different types of proteins such as the cytokine receptor family (interferon), the GM-CSF family and the GP130 receptor family. The JAK kinases occur in four isoforms, with two matching phosphorylation domains, one for activity one for regulation. JAK2 in been shown to be mutated in several conditions including thrombocthemia and myeloprliferation disorders. In relation to haematological maliganacies the JAK2 mutation have been shown to essential for tumor growth and proliferation. Inhibiting the JAK2 kinase offers a potential mechanism for chemotherapeutic action. Ruxolitinib is a small, molecule inhibitor that has been established to inhibit the Janus kinases; early clinic work established that Ruxolitinib has sufficient anti-tumor activity to warrant further investigation. [Read the Full Post]

SB-431542 – MEDIATING ALK INHIBITION IN TUMORS

5117 views | Mar 13 2012

Introduction: Inhibitors of ALK Activin receptor like-kinases (ALK1) are defined as being a type 1 receptor specifically for the transforming growth factor ß (TGF-ß) family of proteins. It is recorded that ALK1 expression is found in blood vessels and may be linked to vascular formation. Since tumor growth is dependant on generating a vascular skeleton to support itself ALK1 appears to be a potential target for chemotherapeutic action. Analysis of hereditary hemorrhagic telangiectasia disorders revealed a mutation n the ALK1 gene transcription. ALK is encoded by ALK gene and plays an important role in the development of brain function. Fusion of the ALK gene with other genes such as the nucleophosmin gene or the EML4 gene is can be linked to specifc types of carcinomas. In NSCLC the EML4- ALK fusion is theroised to be the driving force behind the tumor. Inhibition of the ALK, therefore presents itself forward a potential target for chemotherapy. This is confirmed by the EML4-ALK inhibitor Crizotinib which has achieved approval for use in NSCLC patients. Potentially SB-431542 is another small molecule which could make a huge impact since the SB-431542 IC50 has been determined to be 94nM for ALK5, it remains to be determined whether this can be translated into a sucessfuly chemotherapy agent. [Read the Full Post]

AZD2281: THE FIRST PARP INHIBITOR

3964 views | Mar 13 2012

Introduction: PARP Inhibition Poly (ADP-ribose) polymerase (PARP) is an enzyme located in the cell nucleus that regulates apoptosis and controls repair of minor damaged DNA strands. Since DNA mutations are a common function of many clinical diseases PARP is a significant target for chemotherapeutic action. With 17 known members of the PARP family the mechanism of action for PARP’s activity is important to understand. The PARP protein consists of 4 important area’s; the Zinc figures where DNA repair takes place, a caspase cleavage function, a catalytic domain and a modification domain. Chemotherapeutic action is considered to be via the caspase domain or via the DNA repair domain. Inhibiting the repair of DNA strands triggers the automatic functions of cell death. Inhibitors for PARP have been developed and tested pre-clinically demonstrating the effectiveness of this approach. [Read the Full Post]

AV-951 – THE ANTI-ANGIOGENIC DRUG

3113 views | Mar 13 2012

AV-951: Introduction Angiogenesis is the natural biological system for the formation of vascular networks, tumor growth requires materials and energy to grow, a vascular system therefore develops to supply the growing tumor with oxygen and molecules required for cellular construction. Factors affecting angiogenesis include transforming growth factors (TGF-beta), angiogenin, vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF), epidermal growth factor (EGF) as well as TGF-beta and TNF-alpha which either directly or indirectly affect angiogenic processes. The development of small molecule anti- angiogenesis compounds has been reported extensively in literature. Of which the potent AV-951 VEGFR inhibitor, (a multiple tyrosine kinase inhibitor) has been shown to inhibit VEGF receptors 1,2 and 3 as well as c-KIT and PDGFR. AV-951 PDGFR inhibitor is an oral inhibitor given once daily that has demonstrated great potential in renal carcinomas at phase 1, 2 and 3 levels. It is also being investigated in a variety of other tumor types. [Read the Full Post]

BELINOSTAT: THE UNUSUAL HDAC INHIBITOR

4593 views | Mar 13 2012

Introduction: HDAC inhibition In humans, histone deacetylase (HDAC) is a regulatory enzyme located both in the cellular cytoplasm and in the nucleus. Its function is the removal of an acetyl group from both protein and non-protein targets, this removal is usually part of a signaling pathway inducing or reducing various activities within the cell. There are currently 18 isoforms of HDAC known which are classified into four classes. Class 1 are the nucleus HDAC´s (1,2,3&8); Class II HDAC´s (4, 5, 7 & 9) are located in either the cytoplasm, the nuclease or a transitional state between the two. These two classes of enzymes are related by the fact that they require a zinc catalyst for activity. Class III (6&10) and IV HDAC´s (11) do not require zinc for their activity but instead rely on NAD+ for their activity. [Read the Full Post]

B-RAF INHIBITOR AGAINST CANCERS

3202 views | Mar 13 2012

The mechanism of the RAS-Raf pathway In the normal situation cells will live and die on a regular basis, maintaining healthy tissue and organs. To control this process there are several signaling pathway which either stimulate the cell to proliferate or induce the normal sequence of events for cell death (Apoptosis). The pathway which controls cell proliferation, cell differentiation and cell growth is the RAS/Raf/MEK/Erk pathway Growth is initiated by the activation of RAS, which is located in the plasma membrane, by activation of its tyrosine kinase receptor by extracellular growth factors. The RAS protein receptors are on the external face of the cell while signal is conducted inside the cell. Growth factors activate the external RAS protein so the internal root of the RAS protein complexes with Raf proteins activating them. The raf proteins then actively phosphorylates the MEK protein which in turn phosphorylates the Erl protein and cell division /proliferation beginnings. The role of Raf is therefore to carry the signal from the activated RAS and to MEK protein in the cytosole/nuclease to initiate proliferation activity, the signal also acts as a cell survival mechanism. [Read the Full Post]

DASATINIB – THE DOUBLE-EDGED SWORD

4638 views | Mar 13 2012

Introduction: BCR-ABL and SCR targets Researchers are continuously searching for the magic compound which will cure all diseases but most know that this is a physical impossibility. Every disease is different and especially cancers where even tumors of the same site / type can be radically different. In CML, AML and ALL a mutation in two chromosomes has been linked to the onset of these diseases in a proportion of patients. The defect is referred to as the “Philadelphia chromosome”, here a section of chromosome 9 and chromosome 22 have swapped places (translocated). The end result is that chromosome 9 is longer than it should be while chromosome 22 is shorter than it should be. The significance of this change is that the coding for the BCR gene and the ABL gene become mixed up (fused). The protein from this genetic fusion is referred to as the BCR-ABL fusion protein. Studies have shown that this protein is related to the protein kinase super family and has serine / threonine kinase activity, it also has phosphorylation activity for the cytoskeletal enzyme p21 Rac (Cdc42). Imatinib is a small molecule inhibitor of the ABL in Chronic Myeloid Leukemia, Acute Myeloid Leukemia and Acute Lymphoblast Leukemia tumors that has been proven very successful in the clinic. However, patients with the translocated gene demonstrate resistance to Imatinib due in part to the nature of fused BCR-ABL gene. [Read the Full Post]

EGFR INHIBITORS CONTROLLING TUMORIGENESIS

3754 views | Mar 13 2012

Introduction: The EGFR’s role in the HER pathway A major pathway in the regulation of cell growth / death is the HER pathway, this pathway consists of four structurally related proteins primarily located in the cell membrane. The family members consist of HER1 (also known as EGFR), HER2 (also known as ErbB2), HER3 (also known as ErbB3) and HER4 (also known as ErbB4). These receptors consist of an extracellular head and an intracellular tail lying across the cell membrane. Ligands binding to the extracellular receptor induce conformational changes which reveal binding domains within the intracellular tail. Auto-phosphorylation of the tyrosine kinase domain is a result of the HER receptor forming dimers and depending on which of several different ligands induced the change the tail section attracts proteins to initiate signaling cascades to the nucleus. Ligands that trigger this signaling pathway consist of endothelial growth factor (EGF), transforming growth factor alpha (TGFα), beracellulin (BTC), epiregulin (EPR) and amphiregulin (AREG). [Read the Full Post]

TOZASERTIB IN CLINICS FOR AURORA INHIBITION

5073 views | Mar 13 2012

AURORA KINASE INHIBITION AND TOZASERTIB:  Three isoforms of the aurora kinase have been isolated in human tissue (A,B and C) which function on different aspects of the mitosis cycle. Aurora kinases are significant as targets for chemotherapeutic action since they are elevated in many different cancer types. Small molecule inhibitors of aurora kinases, such as VX-680 (Tozasertib), ZM447439 and Hesperadin have been developed and successfully trialed on several cancer groups including breast, colon, prostate and in acute myeloid leukemia (AML). The initial results obtained for the Tozasertib Aurora kinase inhibitor has lead to its advancement into phase 1 and phase 2 clinical trials. [Read the Full Post]

XL880 AS MULTIKINASE INHIBITOR

2913 views | Mar 13 2012

XL880: Inhibition of the VEGF-R/KDR/MET pathway Vascular endothelial growth factor (VEGF) is a signaling protein that is involved in the angiogenesis and vasculogenesis of damaged tissues. Increases in vascular structure are an important part of tumor growth and VEGF is often over-expressed in many forms of cancer. The mechanism of action of VEGF is through binding to the extracellular portion of the transmembrane VEGF receptors which leads to intracellular signaling which control stimulation of endothelial cell mitogenesis, cell migration, increases in  vasodilation and .microvascular permeability. Over-expression of VEGF has been linked to poor prognosis in breast cancer, rheumatoid arthritis, diabetic retinopathy, age related macular degeneration and angiosarcoma. Targeting the VRGF signaling pathway is means of controlling tumor growth and metastasis. One of the ways in which this can be achieved is by inhibition of VEGF or VEGFR with small molecules. XL880 is a tyrosine kinase inhibitor which targets hepatocyte growth factor (HGF) and its endothelial receptor (MET). MET and VEGF co-operate to promote vascularization of tumors. Single therapy treatments against the VEGF pathway initially can be extremely effective but can lose effectiveness over time, the suggestion is that the MET pathway offers an escape route for cell survival when VEGF is inhibited. [Read the Full Post]

RO4929097 – TARGETING NOTCH SIGNALING IN CANCER

6089 views | Mar 13 2012

RO4929097: INHIBIT GAMMA SECRETASE: Gamma secretase is famous protease consists of several subunits complex. This enzyme is also recognized as inter-membrane protease as it cuts trans-membrane proteins. The most eminent gamma secretase example is breakage of amyloid precursor, a protein to produce amyloid beta peptide which is involved in the formation of amyloid plaques in patient’s brain who suffer with Alzheimer’s disease. In the present situation though, we concentrate on the key role of gamma secretase in the Notch protein processing. It has been found as there is link between anomalous notch signaling and many cancers. Hence the idea of targeting those enzymes which are responsible for the processing of Notch protein became the reason of RO4929097 gamma secretase inhibitor discovery. The inhibiting Notch signaling by using RO4929097 GS inhibitor has been confirmed by protein estimation methods like Biuret method etc. [Read the Full Post]

RO4929097 – CONTROLLING NOTCH SIGNALING IN TUMORS

6206 views | Mar 13 2012

Introduction: Gamma secretase Inhibition Gamma secretase is an internal protease enzyme that is a complex of a number of subunits. Its mode of action is to cleave proteins that lie within the membrane-spanning domain, these include the amyloid precursor protein (APP) and the Notch. The Notch signaling pathway processes four different Notch receptors (1, 2, 3 and 4) which span the cell membrane. Upon extracellular interaction with a substrate protein the internal domain is released. This section of the protein then induced a signaling cascade within the cell nucleus to alter gene expression. The function of the various NOTCH proteins is varied but in terms of cancer notch receptors have been demonstrated to be down regulated in basal cells carcinomas and cervical cancers. Notch 1 over-expression is associated with acute T cell leukemia and breast cancer, Notch 3 receptor is over-expressed in 20% of ovarian cancers [5-7] while overexpression of Notch 4 is evident in murine models of breast cancer. The field of research into NOTCH signaling is vast and beyond the scope of this document, simple put there existed evidence that inhibition of aberrant NOTCH over-expression would be an ideal target for chemotherapeutic activity. The development of inhibitors which would affect the action of NOTCH led to the targeting of the Gamma secretase enzyme. Developed by Roche the RO4929097 gamma secretase inhibitor represents a potent novel small molecule that is orally bioavailable. [Read the Full Post]

GSK3 and Alzheimer’s disease

6063 views | Nov 24 2011

Glycogen synthase kinase 3 (GSK-3), as a serine/threonine protein kinase, can contribute to phosphorylating and thus inactivating glycogen synthase, and also been involved in the control of cellular response to damaged DNA. [Read the Full Post]

Effects of dovitinib on cancers

2890 views | Nov 21 2011

As we all know, cancers are always accompanied by pathological abnormality, such as growth, proliferation and migration of cancer cells. Many factors, as the biomarkers and targets, have been reported to be involved in the process, such as VEGF, PDGF, FGF, and their receptors as well as their downstream signaling components. [Read the Full Post]

The hedgehog signaling pathway, as the target in cancer treatment

8727 views | Nov 18 2011

The hedgehog(Hh) signaling pathway is one of the key regulators of animal development and is present in all bilaterians. The Hh family of proteins have since been recognized to involve in many fundamental processes in vertebrate embryonic development and play an important role in regulating cell fate, patterning, proliferation, survival and differentiation of many different regions. In the embryonic period, dysfunction in the Hh signaling pathway will lead to brain, facial and other midline defects such as holoprosencephaly, cyclopia, absent nose or cleft palate. [Read the Full Post]

MK-2206, as an Akt Inhibitor, enhances antitumor efficacy by chemotherapeutic agents

3363 views | Nov 17 2011

Development and maintenance of many tumors have been reported to be associated with abnormal activation of PI3K. Akt is a critical downstream factor of PI3K signaling pathway and is important in promoting cell survival and inhibiting apoptosis. Clinically, Akt activation and overexpression is often associated with resistance to chemotherapy or radiotherapy. Thus, clinically available small-molecule inhibitors of Akt have remarkable potential in cancer treatment. [Read the Full Post]

Roles of sirtuins in the nervous system diseases

6584 views | Nov 16 2011

As is reported in some studies, SIRT1 is expressed in the adult brain, with high levels in the cortex, hippocampus, cerebellum, and hypothalamus. In brain, SIRT2 is a cytoplasmic protein and plays an important role in the formation of myelin sheath and in the myelin-axon interaction. Other members of sirtuins is also found to exist in brain in various forms. Recent research indicates that a neuroprotective role of sirtuins, especially SIRT1 has been observed[1]. In fact, the effects of sirtuins on common neurological disorders has been described previously. [Read the Full Post]

Expression and activity of Sirtuins

5497 views | Nov 15 2011

Sirtuins are a class of proteins that possess either histone deacetylase or mono-ribosyltransferase activity, and the activities are dependent on and regulated by nicotinamide adenine dinucleotide (NAD+). Until now, seven members have been identified as sirtuin 1 (SIRT1) through SIRT 7. Of which, is considered to be one of the determining factors in longevity induced by calorie restriction. [Read the Full Post]

JNK, a potential therapeutic target for the treatment of nephrotoxicity

3455 views | Nov 14 2011

Nephrotoxicity is a poisonous effect of some substances, including toxic chemicals and medication, on the kidneys, and cyclosporine (CsA) nephrotoxicity is one kind of nephrotoxicity. It is reported that the epithelial to mesenchymal transition(EMT) is an important mechanism contributing to the pathogenesis of cyclosporine (CsA) nephrotoxicity by promoting the generation of myofibroblasts. Some studies suggested that he endoplasmic reticulum (ER) stress as a potential mechanism may participate in the modulation of tubular cell plasticity in CsA-induced EPCs[1]. However, the precise mechanisms have not been known. [Read the Full Post]

The antifungi activity of DNA topoisomerase inhibitors

3967 views | Nov 10 2011

Fungal infections represent the invasion of tissues by one or more species of fungi, such as Aspergillus and yeasts. Some fungal infections will trigger the body’s immune system, cause inflammation and tissue damage, and even lead to serious lung, blood (septicemia) or systemic diseases. [Read the Full Post]