MOLECULAR TARGETED DRUGS

PROTEASOME INHIBITORS• Cachexia occurs late in tumor progression and represents a

progressive wasting of the cancer patient's tissues.

• Use of a proteasome inhibitor was speculated to be useful in retarding the widespread degradation of proteins occurring in the tissues of cachectic patients.

• While at least 5 distinct classes of proteasome inhibitors have been developed, most of these have been abandoned because of metabolic instability, lack of specificity, or irreversible binding and inactivation of proteasomes.

• Disulfiram• Epigallocatechin-3-gallate• Salinosporamide A• carfilzomib• Epoxomicin

boronic acid dipeptide that was designed as a specific inhibitor of the peptidase activity present in the 20S core of the proteasome.

Functioning as a competitive inhibitor of serine protease enzyme, Velcade slows down the flux of substrates through proteasomes, which soon become clogged and dysfunctional.

Multiple myeloma because of the known elevated activity of the NF-KB signalling pathway in the myeloma cells

VELCADE

PS-341bortezomib

Affects the NF- signalling pathway

In the presence of Velcade phosphorylation & ubiquitylation of IKB proceed normally, but the ubiquitylated IKB cant be degraded in the proteasomes because the latter have become engorged with unprocessed polypeptides. This leads to an accumulation of IKB in cytoplasm and to the continued sequestration of NF-KB by the IKB molecules that have built up. Thus, NF-KB is prevented from moving into the nucleus and activating expression

• Side effects: • Peripheral neuropathy• Hypotension & Heart

problems• Lung & Liver disorders• GI problems• Neutropenia, Leucopoenia,

Thrombocytopenia• fatigue, weakness• Anaemia• Fever, decreased appetite

• since proteasomes are used by cells to degrade diverse protein species, proteasome inhibitors are apt to harm normal cells as much as cancer cells.

• In spite of this logic, low concentrations of Velcade exhibit great potency in killing cancer cells in vitro, while having minimum or tolerable toxicity against cells from various normal tissues.

CYCLOPAMINE• a natural product of plant origin- Veratrum califarnicum • a potent teratogenic agent• perturbs the Hedgehog-activated signalling pathway. • Cyclopamine acts as an antagonist of Smoothened that prevents it from activating Gli

An inhibitor of Smoothened, termed HhAntag, was synthesized that has 10 times the potency of cyclopamine and is able to pass easily through the blood-brain barrier, with little if any systemic toxicity

PROTEIN KINASE INHIBITORS- GLEEVEC • More than 95% of cases of chronic myelogenous

leukemia (CML) exhibit the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22.

• The genes that were fused through this translocation are ABL and BCR. The Bcr-Abl protein was found to function as a constitutively activated tyrosine kinase.

• Altogether, the domains present in this fusion protein enable it to activate the Ras pathway, the PI3 kinase-Akt /PKB pathway, the Jak-STAT pathway, and transcription factors including Jun, Myc, and NF-KB.

• Low-molecular weight antagonists of the Bcr-Abl tyrosine kinase activity

• The Gleevec molecule associates with the ATP binding pocket of the Abl kinase domain . It binds and stabilizes a catalytically inactive conformation of this enzyme

• No effect on normal bone marrow cells with only minimal side effects registered

• mutations prevent Gleevec from binding to the catalytic cleft, either by directly interfering with its binding or, less directly, by creating a stereochemical shift in the oncoprotein

• Gleevec also inhibit the PDGF-R - chronic myeloproliferative diseases , metastatic medulloblastomas & the Kit receptor-gastrointestinal stromal tumors (GISTs)

EGF RECEPTOR ANTAGONISTS

• The best-characterized inhibitors of the EGF-R tyrosine kinase are the drugs Iressa, also known as gefitinib and ZD1839, and Tarceva, also called erlotinib and OSI-774.

• The two drugs have very similar but not identical properties.

• These two drugs act by blocking the ATP-binding site of the receptor-associated kinase

These low-molecular-weight compounds penetrate into all the interstices of a solid tumor, including those where the far larger antibody molecules may have trouble gaining access.

Mutant EGF-Rs can’t be bound by monoclonal antibodies. These aberrations doesn’t derail the tyrosine kinase inhibitors, which target the cytoplasmic, Signal-emitting domain of the receptor

far easier and less expensive to produce on an industrial scale

Iressa has short lifetime [hours] compared to monoclonal antibodies [ weeks]

Diarrhoea, rash, acne, nausea, vomiting, loss of appetite, nail problems, hair loss, red/sore mouth or throat, or unusual weakness may occur.

• Non-small-cell lung carcinomas (NSCLCs)

• A substantial proportion of NSCLCs that respond to Iressa treatment have been found to carry mutations in the gene encoding the EGF-R that affect the cytoplasmic domain of the receptor. These alterations deregulate & activate the tyrosine kinase function of the receptor, thereby stimulating the downstream Akt/PKB and STAT signalling pathways, which protect these tumor cells from apoptosis.

• As is the case with acquired resistance to Gleevec the EGF-Rs in these NSCLC patients often acquire structural changes that block drug binding

The future: new targets,new drugs, and new approaches• Advances in the understanding of cancer biology

have led to the identification of many novel drug targets.

• Many of the targets being considered reflect deregulated control of cell growth and division.

• Re-establishment of control of these processes with drugs such as signal transduction inhibitors may be associated with far fewer side-effects than traditional cytotoxics.

• The focus has shifted to targeted drug therapies. If scientists can load their cancer-detecting gold nano particles with anticancer drugs, they could attack the cancer exactly where it lives. Such a treatment means fewer side effects and less medication used. Nano particles also carry the potential for targeted and time-release drugs. A potent dose of drugs could be delivered to a specific area but engineered to release over a planned period to ensure maximum effectiveness and the patient's safety.

• As many of the new drugs are orally bio-available, in addition to having low toxicity, more prolonged treatment regimens than with traditional cytotoxic agents may become possible

Thank you