Combination High Throughput Screening

Disease complexity masks the promise of highly targeted single drugs

Biological pathways fundamental to disease are highly complex with each cell type containing a unique network of pathways wired to a specific pathophysiology. Yet for decades, much of pharmaceutical research has focused on generating very narrowly targeted molecules designed to perturb a single disease target. As more highly targeted drugs are evaluated in man, history shows us that perturbation of a single molecular target often has little or no effect. More importantly, we increasingly see the attrition of potentially high value drugs from pharmaceutical pipelines because of a lack of efficacy.

Better efficacy and selectivity is achieved through combinations

At CombinatoRx, we harness the power of networked biological systems to reveal how perturbations of critical yet "silent" targets can be combined to potentially produce a profound medical effect. The application of this concept, embodied by the use of combination screening in phenotypic mammalian cell based assays, affords the opportunity to discover new targets and combination biology in relevant models of human disease. The concurrent deployment of this strategy in varied genetic backgrounds and in multiple cellular pathway and endpoint assays adds a level of sophistication which fosters the insights necessary for effective therapeutic application. The added selectivity achieved through targeting pathway intersections that are fundamentally wired differently in different cell types may lead to improved safety as well as better efficacy.

A powerful platform for combination screening enables our vision

To realize this vision, CombinatoRx has created a fully integrated and highly automated system of customized hardware and software for combination high throughput screening (cHTS™) in phenotypic cell based assays. This technology platform coupled with our elite library of molecules covering the most important targets in human disease enables combination screening at a scale never before achieved in our industry. Together with an unparalleled analysis platform capable of recognizing and quantifying synergistic drug combinations and integrating complex disease, pathway, target and drug information, our platform enables the discovery of new combination biology, the definition of specific target pairs for therapeutic development and demonstrates the incredible power of cHTS™.

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Calcium Channel Blocker Discovery

Oral CCBs could revolutionize pain treatment

Oral N-type calcium channel blockers have the potential to become a promising new class of pain drugs. CombinatoRx is developing compounds that block the N-type calcium channel, an important target directly linked to pain signal transmission. For decades there has not been a novel oral pain drug, only variations of existing medications. We believe N-type calcium channel blockers have the potential to change how we treat pain and the potential to produce a new class of effective and safe oral medications.

CombinatoRx is also uncovering the therapeutic potential of T-type calcium channel blockers, a target for the development of drugs for the treatment of pain, epilepsy and hypertension. We have identified novel gene targets for T-type calcium channels, found in brain, heart and endocrine cells.

With proprietary molecular and in-house expertise, CombinatoRx is at the forefront of this innovative technology for treating pain. Coupling sound science with a leading team of researchers and developers, we believe we can create new valuable medicines bringing hope to millions of pain sufferers worldwide.

The CombinatoRx N- and T-type compounds derive from a rational drug design process that has successfully led to the discovery of high affinity, selective and orally available calcium channel blockers. Distinguishing itself from its competitors, who rely on more standard approaches such as mass screening, CombinatoRx uses electrophysiological screening in its evaluation process. Electrophysiology allows us to develop state and frequency dependant blockers. It is anticipated that by improving the selectivity of the N-type block in this way, compounds with good safety and tolerability profiles can be developed.

For more information on Calcium Channel Blocker Discovery, click here.