Kinase Inhibitors: beyond Oncology

We recently published a paper in Bioorganic and Medicinal Chemistry, targeting Interleukin-2 inducible T-cell kinase (ITK) for treating Asthma. 

Protein kinases are prime targets for anticancer therapies, but achieving specificity for a particular kinase is challenging because of their close structural similarities. This leads to unwanted side effects, and the toxic outcome may also be due to the result of tissue distribution of kinase inhibitors. Imatinib has been highly successful in treating both chronic myelogenous leukemia, gastrointestinal stromal tumors, and other cancers but is associated with severe cardiotoxicity. Toxicity may be of less concern with oncologic kinases; what about non-cancer indications? Emerging clinical evidence (Nature Drug Discovery) of oral kinase inhibitors other than cancer shows that kinases could effectively inhibit the number of inflammatory pathways.

Almost all the p38MAPK inhibitors having hepatotoxicity issue. For example, SCIO 469 and Arry 797 initially developed for RA but went into the clinic for post operative dental pain; here, the potential toxicity problems will not show up because the drugs are used only for a very short time. Are BMS-582949 and VX 702 still in development? Different companies have spent hundreds of millions on P38 with nothing to show at the end.

Tasocitinib may be the first kinase inhibitor (JAK3) for non-oncology indication and the first oral DMARD for RA in a decade if it successfully completes Phase III clinical trials.

Naked Discovery

Unlike the highest secrecy in closed-door traditional drug discovery by the pool of rigid mindset scientists, the Open Source Drug Discovery (OSSD) Program aims to address the issue by capturing the youngest and brightest minds around the globe to be a part of developing drugs to treat diseases such as drug-resistant TB and malaria, and HIV. Open-source software may have been around for many years, but using an open-source model to speed up drug discovery is a relatively new idea

"Research labs in India are filled more with technicians, as opposed to creative minds. "You really don’t need to have a doctorate in pharmacy to contribute to developing a drug" said Samir Brahmachari, Director General of India’s Council of Scientific and Industrial Research (CSIR), and he believes that the OSDD can be as successful as Linux or a Wikipedia.

Tuberculosis kills at least 3,30,000 Indians annually and 1.7 million people Globally. The incidence of multi- and extensively drug-resistant strains of TB ( MRD- and XRD- TB ) demands renewed efforts to develop a novel class of fast-acting anti TB chemotherapeutics. Recently, Indian scientists have mapped the Mtb tuberculosis genome under the OSDD initiative of CSIR, giving hope of discovering new drugs for TB. This is the first time that the Mtb genome's comprehensive mapping has been accumulated, confirmed, and made available publicly.

This Connect to decode‘S (C2D) finding may contain critical data to unlock previously undiscovered details of TB, resulting in development opportunities for urgently needed new drugs in India and other developing countries.

Retropharmacology: From Drug to lead

Drug discovery is a lengthy, high-risk, and costly endeavor; many strategies are available to accelerate the development process to provide high-quality drug candidates. The diminished interest in Natural products drug discovery as the industry embraced promising and exciting new technologies, particularly combinatorial chemistry. However, these new technologies promise to fill the drug development pipeline with small-molecule candidates is unfulfilled. Learning from the past with the appropriate strategy for the future is essential to make a significant difference.

Valerian has been used as a medicinal herb science at least the time of ancient Greece and Rome as a sedative, migraine treatment, pain reliever, insomnia, and other disorders as an alternative to benzodiazepine drugs.

Valerenic acid, a significant constituent of common valerian, is a potent modulator of  GABA-A receptors. In order to develop a broader understanding of structural requirements for GABA-A modulatory activity of valerenic acid. Kopp et al. (chem med chem) synthesized several analogs and found that some of the derivatives such as tetrazole (pic) are proved to be the most potent allosteric potentiators of GABA-induced ion currents, and its activity exceeds the activity of valerenic acid and Diazepam.

This reverse pharmacology approach, relates to reversing the routine ‘laboratory-to-clinic’ progress to ‘clinics-to-laboratories’ (inspired by traditional medicine), can offer a smart strategy for new drug candidates.

The rise biopharmaceuticals

The movement of big pharma into biologics  (biopharmaceuticals) understandably has a direct effect on the pharmaceutical landscape. Companies show a diminishing portfolio revenue from small molecule drugs, primarily because of patent expiration on blockbuster drugs (small molecules) and the reallocation of industry resources towards biologics.

Biologics represent one of the most promising frontiers in pharmacotherapy; USFDA approved more biologics in 2009, the figure includes 19 new molecular entities (NMEs) and six novel biologics. In 2008 FDA approved 21 NMEs and three novel biologics. A substantial improvement in biologics approvals in 2009. (fig.1, Nature Medicine, 139, 16, 2010). Moreover, it is expected to take over from small molecule field in the coming years (fig 2, Nature reviews / drug discovery). However, their cost can be substantial, reaching $200,000 or more annually for treatment (Cerezyme), and the large molecules drugs are administered via injection – a less popular option with patients.

Biologics are gradually going to replace the traditional approach to drug design. Students need to understand industries changing needs if they plan on carriers in this area.

Kill the Bugs, Selectively

“Today, we have tuberculosis drugs you have to take for nine months, why can’t we find one that works in three days” - Bill Gates. 

Tuberculosis (TB) is a chronic contagious disease caused by  Mycobacterium tuberculosis (M.tb), one of the leading causes of death worldwide. The WHO estimates about one-third of the world’s population is infected with M.tb, 10% of those infected will progress to active TB disease during their lifetime. The tuberculosis pandemic has been declared a global health emergency as the growing resistance of M.tb to Antibiotics coincides with the spread of risk factors such as HIV/AIDS and diabetes. TB is a complex disease. The current TB drug regimen, a product of scientific advances of the 1960s, requires six to nine months of treatment for active, drug-susceptible TB. Unfortunately, many patients do not or cannot complete this treatment. Poor adherence and prescribing practices have led to the emergence of multi- and extensively drug-resistant strains of TB (MDR-TB and XDR-TB) that increasingly defy current medicines and spread throughout many regions of the globe. The incidence of MRD- and XRD- TB demands renewed efforts to develop a novel class of fast-acting anti TB chemotherapeutics.

 

Mycobacterium tuberculosis is one of the few bacterial species with a proteasome. A team of scientists led by researchers from Weill Cornell Medical College  has found that some oxathiazolone compounds kill tuberculosis-causing bacteria by selectively inhibiting mycobacterial proteasomes without affecting human proteasomes. These compounds were showing no apparent toxicity to mammalian cells. The oxathiazolone compounds are the first example of an anti-tubercular agent that inhibits protein breakdown. The ability of brief exposure to oxathiazol-2-one compounds to inhibit M.tb proteasomes permanently makes it a potential target for anti-TB therapy. These  findings  may lead to drugs that destroy TB in the dormant stage of the lifecycle.