User:Tristankleyn/Proteus Discovery, inc.

Proteus Discovery, Inc. is a therapeutic development company for genetically linked diseases based in Cambridge, Massachusetts, USA. Since their 2012 launch, Proteus' focus is on finding solutions for Parkinson's disease through the use of unique Schrödinger software to accurately determine the structures of specific proteins involved in genetic diseases such as Parkinson's and Crohn's.

Technology
The Proteus team has developed a computationally driven high-throughput screening technology that enables early insight into protein specificity and therapeutic selectivity. Proteus’s approach selects in silico a chemical library of candidates using [schroedinger_details?]. This intelligent library is screened at high density across a proprietary chemical library in a highly parallel process. In collaboration with Harvard and Schroedinger, the team has developed insight into a novel class of LRRK2 inhibitors.

Early protein kinase inhibitors targeted the ATP binding site, but these “Type I” inhibitors are characterized by strong side effects. Second-generation inhibitors targeted an allosteric site that locks the kinase into an inactive state. These “Type II” inhibitors tend to be more selective because they avoid the ATP binding site, which is common to all protein kinases.

Studies showed that Type II inhibitors of LRRK2, such as imatinib (Gleevec), were able to inhibit wild-type LRRK2. However, these inhibitors had almost no effect on G2019S or I2020T mutants, the two most prevalent mutants among PD patients. Proteus focuses on a novel class of LRRK2 inhibitors that will be both highly active toward G2019S and I2020T mutants as well as highly selective against other kinases.

Using a multidisciplinary approach that combines molecular simulations, structural biology, medicinal chemistry, and in vivo experiments, our team recently discovered that the G2019S and I2020T mutations lead to a thermodynamic stabilization of the activated state of LRRK2 that diminishes the effect of traditional Type II kinase inhibitors. In short, these mutations lock LRRK2 into a conformation that prohibits traditional Type II inhibitors from binding. While Type I inhibitors can still bind and inhibit LRRK2 activity, they lack specificity and often have severe side effects due to non-selective interactions with other kinases.

From this insight, Proteus is screening a population of small molecules that we have identified as promising drug candidates through computational discovery. Leveraging the Schrödinger partnership and our collaboration with Harvard’s LNND, our high throughput selectivity screening infrastructure provides a platform from which to develop a novel class of LRRK2 inhibitors (called “Type III” inhibitors) that will be effective against the G2019S and I2020T mutations in addition to having a desirable selectivity profile as a result of avoiding the ATP binding pocket.

This novel approach offers a unique platform for early therapeutic hit discovery across a range of genetically linked diseases and beyond.

Team

 * •	Karl Ruping, Founder & Chief Executive Officer
 * •	Patrick Kleyn, Founder & Chief Scientific Officer
 * •	Soumya Ray, Founder & Science Director

LRRK2
Proteus’ first program is focused on Leucine-rich repeat kinase 2 (LRRK2) protein. LRRK2 is a member of the protein kinase family. Protein kinases are enzymes that catalyze the transfer of phosphate groups from high-energy ATP to other proteins in a process called phosphorylation. The human genome contains approximately 500 protein kinases (~2% of the genome) and up to 30% of all human proteins may be modified by protein kinases.

While Parkinson’s Disease (PD) is traditionally considered a non-genetic disorder, recent studies have show that LRRK2 is directly linked to the disease. People with particular LRRK2 mutations will most likely develop PD within their lifetime. Parkinson’s disease (PD) is a debilitating brain disorder that occurs when dopaminergic neurons in the substantia nigra region of the brain become impaired. The resulting decrease in dopamine production leads to impaired coordination, tremors, muscle rigidity, and eventually cognitive deterioration. The common treatment is levodopa or l-DOPA, an off-patent generic that stimulates dopamine production. Long-term use, however, leads to reduced effectiveness and serious side-effects such as rigidity and involuntary muscle movements (dyskinesias). Improvements have been limited to dopamine agonists and dopa-decarboxylase inhibitors which increase efficacy, but neither overcome the side-effects and eventual resistance faced by advanced patients.

LRRK2 mutations are also implicated in Crohn's Disease (CD), a type of inflammatory bowel disease that results in abdominal pain, diarrhea, and vomiting. Similar to PD, there is no preventative therapy or cure for CD and current treatment is limited to controlling symptoms, maintaining remission, and preventing relapse.

The Proteus team has developed a detailed molecular understanding of two of the most prevalent disease-related LRRK2 mutations, G2019S and I2020T. With this insight and our parallel drug discovery/drug design platform, Proteus is pursuing a novel class of LRKK2 modulators that demonstrate specificity and selectivity. The initial focus is CD where, despite a relatively small US patient population of 500,000, the global market is $3.6 billion. A similar approach is possible for patients with familial PD, as well as pre-Parkinson’s patients that carry LRRK2 mutations. There are over 6 million PD patients worldwide, leading to a $2.7 billion therapeutic market, with 1.5 million patients in the US alone.