Gilenya: A Novel First in Class Oral Drug Approved for Multiple Sclerosis Treatment

A natural product inspired/derived first in class oral drug fingolimod (Gilenya) was approved by FDA for treating multiple sclerosis. This drug pocess novel mechanism of action compared to other drugs with immuno modulation. It is a structural analogue of myriocin, a sphingosine metabolite isolated from the fungus Isaria sinclairii. Fingolimod get phosphorylated with sphingosine kinases mainly sphingosine kinase-2 and binds to extra cellular G-protein coupled receptors mainly sphingosine-1-phosphate receptor S1PR1. It then prevents sequester lymphocytes in lymph node and preventing them from moving into central nervous system and stops the damage. A complete story was published on fingolimod in a recent Journal of Natural Products article

Pazopanib: A new drug for treating renal cell carcinoma

In October 2009, US FDA approved a new therapy for renal cell carcinoma. This was highlighted in Nature Reviews: Drug Discovery January, 2010 issue. Complete priscription information given on FDA web site.

Discovery to Delivery: Future of Cancer Research

Nice video town hall discussion about future cancer research, little old one but good one on Future Cancer Research. Genentech focusing on anti-body conjugates for targeted specific delivery and pro apoptotic agents are undergoing clinical trails. In addition, Hedgehog signaling pathway also targeted to find cure for skin cancers.

Obesity-Free Fatty Acids Derived Immune Problem?

In bacterial/viral infected human body, bacteria/viral toxin surface lipo poly saccaride (LPS) generally recognized through a type of receptors called Toll-Like Receptors (TLRs). Especially LPS recognized using TLR-4. Once body recognize the bacterial toxin, it prepares to attack them and creates immunity against it by passing this information to immune cells macrophages. These cells produces cytokines TNF-alpha, IL-6 (a kind of toxic proteins) also leads to activation of NF-kb and JNK1 pathways and inflammatory response. Continuation of this infection leads to severe inflammatory diseases with multiple organ failures.

In western diets prepared using vegetable and animal oils, a plenty available common fatty acids (palmitic/stearic acid) also have good tendency to bind like LPS on Toll-Like Receptor-4 (TLR-4) in humans, this produces similar inflammatory response by cytokine release and activation of NF-kb and JNK1 pathways. Once JNK1 activates, it phosphorylates Insulin Substrate Receptor-1 (IRS-1), which interfere with insulin signaling. Continuation of this Free Fatty Acids (FFAs) activation leads to human whole body inflammation (obesity), insulin resistance/type 2-diabetes and organ failures.

Autophagy: The Active Process Behind mTOR Inhibition and Calorie Restriction

Today an intersting news came out about a long term study of calorie restriction in higher animals (monkeys). Interstingly calorie restriction increased 10-20% life span. Autophagy (a kind of cell suicide) activated in both mTOR inhibition with Rapamycin and calorie restriction conditions, where some of our body cells (adipose tissue/fat) open up and used for generating energy to the body. In other way, if we stop this process by excess feeding, a kind of stress (ER stress) generated. This sustained stress leads to pancreas beta-cell failure and metabolic syndrome (diabetes, high blood pleassure, cardiovascular disease). High fat deposits also leads coronary heart disease. Calorie restriction and exercise helpful to improve this condition.

Changing Trend: Magic Bullets to Designed Multiple Ligands (DMLs)

The concept of selective inhibitors (Magic Bullets) one drug-one disease is no more an ideal in drug discovery. Knocking down one protein target is not enough to treat complex diseases like cancer. If we knock down multiple targets in a biological pathway of a disease with Designed Multiple Ligands (DMLs), we may expect improved efficacy. The trend in recent developments in anticancer drug discovery shifting towards a multi-target approach. One good example is recent wave of FDA approvals, "lapatinib" a dual EGFR and Her-2/neu kinase inhibitor. The other one “dasatanib” a multi kinase inhibitor and many more.

Pharmaceutical "GOLD RUSH"

At last spring ACS meeting, I attended for BMS-Smissman award talk by a renowned scientist Bruce E. Mayanoff. His talk related to the true life stories in drug discovery, which also appeared in J. Med. Chem., ASAP. His observations are certainly true in industry. Nowadays, scientists like Bruce Maryanoff kind of attitude are very rare. Modern scientists have more faith on fast track drug discovery by process of doing it. No focus on real medical need, only rush..."GOLD RUSH" following behind each other. Good science leads to best used drugs. Read more on this topic at Org Prep Daily as well.

Inverse In Silico Screening for Identification of Kinase Inhibitor Targets

Nice article about in silico prediction of targets of a kinase inhibitor, which immensely facilitate and accelerate drug development. Using a virtual inverse screening approach, where single compounds are docked into protein structures from a database, to identify new targets for known inhibitors.