Category

Archives

Blog of Signaling Pathways

SB-431542 – MEDIATES ALK INHIBITION

4722 views | Mar 20 2012

ALK (ANAPLASTIC LYMPHOMA KINASE) RECEPTOR: Anaplastic lymphoma kinase or ALK is encoded by ALK gene and it is also called as CD246 (Cluster of Differentiation-246). This kinase is famous for the brain development but by the genetic fusion of any other gene it can be an oncogenic gene, another reason for its genetic variability is due to the normally found mutations of DNA. In case of ALCLs or large cell lymphomas, NPM (nucleophosmin) is present in fusion form with ALK and this is responsible for the 60% of this cancer. In some of the other cancers like NSCLC (non-small cell lung cancer) and most of adenocarcinomas, the ALK-EML4 fused genes are found as the main cause of tumor formation. Similarly in a pediatric cancer that is known as neuroblastoma, mutated ALK is reported as the main reason in various studies. All of these important examples enlighten the significance of this pathway in different cancers and tumors therefore the discovery or development of such compounds which inhibit the ALK TKs pathway is important. Certain approved inhibitors like Crizotinib used for lung cancer treatment enhances the uses of different inhibitors found in inhibitor library including SB-431542 ALK inhibitor. [Read the Full Post]

SORAFENIB: THE MULTIKINASE INHIBITOR

0 views | Mar 20 2012

INTRODUCTION: By using multi-kinase inhibitors, more than one kinase enzyme at a time can be targeted so their use is considered to be very important and practicable approach for the treatment of cancers. Hence the use of a single inhibitor molecule having pan-tyrosine kinase ability is very attractive to target different overexpressed tyrosine kinases simultaneously. A lot of such inhibitor molecules are being used for this purpose which is showing very promising results in clinical trials. The property of Sorafenib VEGFR inhibitor is that it targets many other receptor molecules other than VEGFR. Sorafenib B-RAF inhibitor inhibits different pathways like Raf/MEK/ERK very efficiently which approves it’s as a multi-kinase inhibitor. [Read the Full Post]

OLAPARIB: THE FIRST PARP INHIBITOR

4545 views | Mar 19 2012

Introduction: PARP Inhibition Signaling activities within the cell are conducted along set pathways of protein – protein interactions. Depending on the cell status and the ligands triggering the signaling cascade to what function is carried out in the nucleus. A protein located in the nucleus has been established to be the principle regulator of the apoptosis and repair functions of certain DNA damage. This protein is called “Poly (ADP-ribose) polymerase” or it is abbreviated to “PARP”. The PARP family of proteins is extensive with 17 members currently known and the range of effects of PARP activity is large. The general structure of the PARP series of proteins contains four different types of binding domains which dictate the activity, one of the domains is referred to as the catalytic domain contains an amino acid sequence that is identical between all the members of the protein family. The mechanism of action of PARP proteins is to add a series of ADP ribose molecules to the protein ligands, the number and site of this addition controls the response of the affected protein. [Read the Full Post]

U0126: THE MOST POTENT MEK INHIBITOR

5263 views | Mar 18 2012

The MAPK pathways In ever cells life span there are circumstances when the cell is placed in a stressful situation, such toxic shock, injury to the surrounding tissue or old age. In such circumstances the cells must react either to die or to live and grow. The regulation of this process is the responsibility of the “Mitogen-activated protein kinases (MAPK)”. The MAP kinases are involved in a broad spectrum of processes covering proliferation (mitosis), apoptosis, cell migration/motility and gene expression. The MAP kinases are located in the cell membrane and on receipt of an external extracellular signal any one of three pathways can be stimulated, these are the ERK, JNK or the P38MAPK pathways. [Read the Full Post]

TEMSIROLIMUS

2465 views | Mar 18 2012

Introduction: mTOR inhibitiors The mTOR kinase is part of the same pathway as AKT and PI3K, this signaling pathway is a tyrosine kinase sub family of the super protein kinase family. The PI3K/AKT/mTOR signaling cascade is involved in a variety of cellular functions such as migration, growth, protein synthesis, survival and proliferation. PI3K and AKT inhibitors have all been reported as having significant potential as treatments against disorders involving cell growth, mTOR is part of the same pathway and theoretically would make a potential target for inhibition. It has also been reported that mutations in the mTOr signaling have been implicated in cardiovascular disease, cancer and disorders of the metabolism. Rapamycin was the first mTOR inhibitor to be released but was quickly followed by a 2nd generation analogue Sirolimus. Temsirolimus is a 3rd generation molecule designed to be an improvement over rapamycin and Sirolimus. Temsirolimus has demonstrated potential in the treatment of renal carcinomas, NSCLC and malignant glioma. [Read the Full Post]

OBATOCLAX AGAINST BCL-2 PATHWAYS IN CANCER

3269 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

4010 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

5428 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

4558 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

2879 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

3526 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

3049 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

4032 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

3308 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

4172 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

3697 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

4247 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

4148 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

2858 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

3893 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]