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ESKM, a novel therapeutic agent for sensitive and resistant PH+ leukemias

The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients

Effects of PARP inhibitors in BRCA gene-mutated ovarian cancer

DASATINIB; An inhibitor of Receptor Tyrosine Kinase

GP130/JAK/STAT3 signaling pathway induces multiple myeloma

Blog of Signaling Pathways

OBATOCLAX AGAINST BCL-2 PATHWAYS IN CANCER

3703 views | Mar 13 2012

Importance of Bcl-2 Pathway in Cancer: The pro-survival protein Bcl-2 and its related family members activate pro-survival pathways in cancer that are often associated with uncontrolled proliferation of cancer cells. Apart from this direct effect, stress pathways are also reported to be converging with Bcl-2 signaling pathways which makes the development of various Bcl-2 inhibitors an attractive approach to target cancer by inducing mitochondrial apoptotic pathways. [Read the Full Post]

OLAPARIB FOR PARP-1 INHIBITION

4445 views | Mar 13 2012

PARP-1 Inhibition and its Implications in Cancer: The Poly [ADP-ribose] polymerase 1 or PARP-1 proteins have been well documented to be linked with cancers affecting their differentiation, proliferation and transformation. On the other hand, BRCA1 and BRCA2 genes are also well linked with the highly proliferating ovarian and breast cancer and hence the development of PARP-1 inhibitors that can target the aforementioned genes effectively in breast and ovarian cancer cells has been considered as a very attractive and feasible approach. The increasing popularity of PARP-1 inhibitors can be attributed to their specific action against cancer cells while sparing normal cells. [Read the Full Post]

AZD1152 – AN AURORA KINASE INHIBITOR

6017 views | Mar 13 2012

Inhibition of AURORA KINASES in relation to cancer: Mitosis is a key process in the regeneration of cellular material and two key regulators of this function are serine and threonine kinases which are more commonly known as Aurora Kinases. 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). [Read the Full Post]

ABT-263: THE BH-3 MIMETIC

4995 views | Mar 13 2012

ABT-263 – Introduction: ABT-263 is a small molecule Bcl-2/Bcl-XL inhibitor marketed by Abbott laboratories under the generic name of Navitoclax. Similar in nature to ABT-737, also marketed by Abbott laboratories, ABT-263 inhibits the anti – intrinsic apoptotic pathway via the BH3 domain. Bcl-2/Bcl-XL bind with pro-apoptotic proteins (BID) with the single BH3 domain and thereby regulate the apoptotic process. However, it has been observed in numerous cancer types that Bcl-2 is over expressed which leads to the survival of cells that would normally be removed via apoptosis. ABT-263 Bcl-2 inhibitor have been demonstrated to be effective against small cell lung cancer xenographs, acute lymphoblastic leukemia and hematologic tumors. [Read the Full Post]

ABT-869 – THE MULTI KINASE INHIBITOR

3258 views | Mar 13 2012

ABT-869 – Tyrosine Kinase Inhibition: Tyrosine kinase is a family of enzymes that utilize phosphorylation of proteins to determine activity of many cellular functions. Tyrosine kinases are a sub family of the protein kinases which phosphorylate serine and threonine for cellular control. Mutation at the genetic level has been observed in this family of enzymes, which leads to the enzyme becoming unregulated. This over expression is observed in many cancer cell lines and represents a target for chemotherapy treatment. Tyrosine kinase inhibitors are novel small molecules which have come to the forefront of cancer research in recent times. Based on the designed molecule Imatinib, TKI’s have been developed to inhibit a wide range of tyrosine kinase receptor either as a single targeted or as a multiple targeted drug. ABT-869 PDGFR inhibitor, marketed under the trade name Linifanib, is a multi-targeted inhibitor against PDGFR-β, KDR, CSF-1R, FLT1, FLT4, KIT, FLT3 and Tie2. [Read the Full Post]

BCL-2 INHIBITOR – SMALL YET EFFECTIVE

3977 views | Mar 13 2012

INHIBITION OF BCL-2 PROTEINS: Apoptosis is the natural system for the removal of cellular material from the body. This could be due to damage by invasion, age or injury. There are two mechanisms which regulate this process, the Intrinsic and the Extrinsic pathways. The extrinsic pathway is a cascade of signal originating from outside the cell via death receptors on the cellular membrane. The intrinsic pathway is initiated within the cell whereby pro-apoptotic proteins are released to activate the caspase cascade from the mitochondria. Part of the caspase cascade is the family of Bcl-2 proteins which regulate the process towards apoptosis or survival. Bcl-2 family consists of anti-apoptotic members such as Bcl-2, Mcl-1, Bcl-XL and Bcl2a1, other members are the pro-apoptotic proteins such as BAX, BAK, BAD, BIM, PUMA, BID, BIK, NOXA and BMF. In many forms of cancer it has been demonstrated that Bcl-2 is over expressed such as lung, breast, prostate, renal, ovarian and glioblastoma cancer, melanoma and leukemia are the highest report over expressers of Bcl-2. [Read the Full Post]

AMG706 – Multi targeted broad spectrum inhibitor

3535 views | Mar 13 2012

AMG706: MULTI KINASE INHIBITOR Tyrosine kinases are a family of enzymes which fuction as regulators of many cellular processes but the phosphorylation of proteins. This process involves the action of ATP, the kinase and the target protein complexing for the transfer via a ATP binding domain on the tyrosine kinase. Computer simulation of the conformational structure of tyrosine kinases led to the development of a highly specific molecule which inhibited the phosphorylation by preferentially binding to the receptor domain. This molecule was determined to be very successful clinically in the treatment of chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs). Imatinib is single kinase inhibitor but market driven forces have developed many tyrosine kinase inhibitors that either target single kinases or multiple kinases. [Read the Full Post]

ABT-737: THE SMALL BCL-2 INHIBITOR

4389 views | Mar 13 2012

BCL-2 INHIBITION AND ITS IMPLICATIONS: Bcl-2 family of proteins are a series of regulator proteins governing the pro-survival pathway. Characteristically Bcl-2 has been discovered to be over expressed in a variety of tumor types such small cell lung cancer, melanoma, prostate and breast cancer. The concept of targeted chemotherapy is to focus drug inhibition against a target that is over expressed in the cancer cell in comparison to normal cellular material; Bcl-2 is a clear target for inhibition. Over expression of this protein disrupts the regulation of the intrinsic apoptotic pathway, creating chemotherapeutic resistance. By inhibiting the sequestering of pro-apoptotic proteins by the Bcl-2 family (anti-apoptotic proteins) normal apoptotic processes can be utilized to trigger tumor cell death. Significantly there have been several now molecules introduced into the clinic in recent years which target Bcl-2 and have demonstrated clear benefits in chemotherapeutic action. One of these small molecules is ABT-737, while others are Navitoclax (ABT-263), Obatoclax (GX15-070) and TW-37. [Read the Full Post]

SORAFENIB: THE MULTIKINASE INHIBITOR

3812 views | Mar 13 2012

SORAFENIB INTRODUCTION: Sorafenib is a member of the class of compounds referred to as tyrosine kinase inhibitors. Developed originally as a Raf inhibitor the Sorafenib RAF inhibitor proved to be effective against more than one tyrosine kinase. Sorafenib demonstrated abilities to inhibit both tumor progression kinases and tumor angiogenesis kinases. As a direct result of the multiple targeting of this compound the Sorafenib PDGFR inhibitor has demonstrated activity in a wide range of cancer types such as renal cell carcinoma, breast cancer, hepatocellular carcinoma and colorectal carcinoma. Sorafenib is currently one of only 10 tyrosine kinase inhibitors approved for clinical use under FDA rulings (2005 – advanced renal cell carcinoma, RCC; 2007 – in inoperable Hepatocellular carcinoma, HCC), in addition Sorafenib has been approved by the European Medicines agency for use in HCC and RCC where first line therapy has failed. [Read the Full Post]

AKT INHIBITORS AGAINST TUMOR GROWTH

4734 views | Mar 13 2012

AKT PATHWAY AND ITS LINK WITH CANCERS: With the emergence of the tyrosine kinase inhibitors attention was directed toward Akt, a serine/ threonine kinase of the protein kinase family. Akt is more formally known as protein kinase B and exists in three isoforms. Its role in the cellular signaling cascades has been well documented with downstream effects on mTOR, BAD and GSK3 The PI3K/Akt/mTOR pathway has been established as having an important role in apoptosis, cell migration and proliferation, transcription and glucose metabolism. In various known forms of malignancies Akt has been established as playing a crucial role, an elevated expression of phosphorylated Akt is a contraindication of survival. Hence focus was placed on the development of AKT inhibitor drugs. AKT inhibition has been achieved with Perifosine, MK-2206, RX-0201, Erucylphosphocholine (ErPC), PBI-05204, GSK690693, A-443654 and XL-418. [Read the Full Post]

SUNITINIB: THE MULTI-TARGETED APPROACH

4167 views | Mar 13 2012

SUNITINIB: A Multikinase Inhibitor Sunitinib is an oral, small molecule of the protein kinase subfamily called Tyrosine Kinase’s (TKI’s). Tyrosine kinases functions by the phosphorylation of a target protein utilizing ATP as its source. Phosphorylation of the target protein simulates either “on” or “off” in terms of activity. Unregulated activities of tyrosine kinases have been linked to many cancer types, leading researchers to develop strategies to inhibit specific Tyrosine kinase activity. TKI’s began to to be developed and tested pre-clinically in the late 1990’s and early 2000, several have reached fast track approval status due to the success of early trials. Sunitinib is one of the currently approved drugs and is approved for renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) as early as 2006. Sunitinib is the only TKI that has been approved for two different indications. [Read the Full Post]

Axitinib – A novel tyrosine kinase inhibitor

4776 views | Mar 13 2012

Introduction Axitinib (AG-013736) is a small molecule 2nd generation inhibitor of tyrosine kinases (TKI). The unique aspect of this type of inhibitor is that they are orally administered yet remain a selective inhibitor of tyrosine kinases. Axitinib is a multi targeted inhibitor focusing on vascular endothelial growth factor receptors 1, 2 and 3 (VEGFR-1,2 or3), platelet derived growth factor receptor (PDGFR), and cKIT (CD117). VEGF is a functional part of the angiogenesis and vasculogenesis pathways and is frequently observed to be over expressed in various oncological conditions but not in normal tissue. Targeting molecules to inhibit tyrosine kinases represents a new novel approach to chemotherapy and over 50 such molecules have been developed for clinical use, 10 of which have been approved for clincal use. Axitinib is a pyrimidine core structure based on the first generation drug Imatinib., Imatinib was the first TKI to be approved for clinical use, it is used in the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). Axitinib is still under development by Pfizer inc, originally called AG013736 it is currently undergoing several phase 1 and phase 2 trial in renal carcinoma. [Read the Full Post]

ANGIOGENESIS INHIBITORS TACKLING VASCULARIZATION

4608 views | Mar 13 2012

THERAPIES AGAINST ANGIOGENESIS: During normal cellular growth patterns new blood vessels are formed to provide a vascular network to enable nutrients and oxygen enter and for waste to leave the system. This process is referred to as Angiogenesis. Tumors are unregulated cellular growths but they still require oxygen and nutrients to be able to grow, depriving tumors of either oxygen or nutrients would halt tumor growth or trigger tumor reduction through apoptosis. Since tumors are unregulated growth they require a more efficient or extensive vascular system than normal tissues hence angiogenic processes represent a possible chemotherapeutic target with angiogenesis selective inhibitors. Research has demonstrated over twenty different factors that regulate angiogenic processes providing a rich source of potential targets for angiogenesis pathway inhibitors. These all angiogenesis antagonists and either directly or indirectly affect the angiogenic processes. Angiogenesis inhibition takes advantage of known factors to develop precisely-structured proteins with known biological effects. Angiogenesis inhibitor drugs. can consist of small molecules such Marimastat or modified proteins such Bevacizumab. [Read the Full Post]

ROSCOVITINE – CONTROLLING THE CYCLINS

3252 views | Mar 13 2012

Introduction: Cyclin-dependant kinase Inhibitors: Another family of proteins that are involved in the regulation of cellular growth are the cyclin dependant kinases (CDK’s). These enzymes are known to be involved in the regulation of the cell cycle (Mitosis (M phase) – Gap phase (G1) – Synthesis (S) – Gap phase (G2)) as well as regulating transcription, mRNA and differentiation of nerve cells. CDK’s contain not much more than a kinase domain and are serine / threonine phosphorylators. The substrate for CDK’s is a regulatory protein called cyclin of which 12 are known. The activity of CDK’s is restricted to the CDK – complex which in human cells there are at least 9 known variations. Different CDK-complexes are involved at different stages of the cell cycle process each one controlling one or more factors. In current theory CDK’s are the diving motivation behind each phase of the cell cycle and deviations in the CDK activity from the normal can cause unregulated proliferation or simple a tumor. Hence direct targeting of the aberrant CDK activity would ideally be a therapeutic possibility. However, with CDK activity essential for all cell cycle processes there was no theoretical distinction between tumor and normal cells hence significant toxicology could be expected. Recently new research changed this theory; it indicated that tumor cell cycle was controlled by an interphase CDK that was specific to the tumor cell. With this inhibitors of CDK activity could now be implemented against tumor growth patterns. For this purpose smaal molecule inhibitors were designed, of which the Roscovitine CDK inhibitor is one of several being tested in certain tumor types. [Read the Full Post]

SKI-606 AGAINST SRC KINASES

4386 views | Mar 13 2012

SKI-606: SRC Inhibitors Tyrosine kinases are a subgroup of the protein kinase super family and have been shown to regulate cell growth pattern, cellular proliferation, angiogenesis, invasion and metastasis in mammalian tissues. Many tyrosine kinases are up-regulated in tumor progression and present potential targets for chemotherapeutic inhibition. The Src kinase is non-receptor tyrosine kinase that includes 3 sub-families (SrcA,SrcB and SrcC). SrcA sub family is made up of Src, Yes, Fyn, and Fgr proteins while SrcB is made Lck, Hckm Blk and Lyn proteins. It has been reported in several tumor types that Src levels are elevated and this rise continues with progression of the disease. Tne mechanism behind Src elevation is not clearly understood and it is theorized that is the product of a “multifactorial process”. To further confuse the issue Src appears to changes its activity based on a direct or indirect interaction with EGFR, PDGFR, FGFR, CSF-1R, HER2 or c-MET. [Read the Full Post]

RUXOLITINIB: THE JACK FOR JAK INHIBITION

7571 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

5672 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

4591 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

3705 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

5268 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]