Plex Pharmaceuticals is a scientifically-driven company with a vision to improve the lives of patients afflicted with complex diseases and disorders including but not limited to Parkinson’s disease, glioblastoma and Cataracts.
Plex has programs to develop modulators of heat shock proteins (Hsp) and FK506 Binding Protein (FKBP) as treatments for proteopathic neurodegenerative diseases (PNDDs) such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig’s disease.
PNDDs comprise a group of CNS diseases characterized by intra and extracellular deposition in neurons and other CNS cells of misfolded protein oligomers, aggregates, fibrils and plaques, all of which ultimately contribute to disease pathology. Some of the most common PNDDs in order of frequency include Alzheimer’s disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS).
One therapeutic strategy aimed at removing or preventing accumulation of misfolded proteins in PNDDs is to target components of the protein homeostasis network (PHN) that include Hsps. The PHN functions both in promoting proper protein folding and in disposal of improperly folded proteins.
Hsps, many of which can readily be stress-induced, are intimately involved as protein chaperones by participating in many stages of protein folding and degradation. Plex’s goal is to take advantage of these properties of Hsps as a targeted approach to treat ALS, PD and other PNDDs.
FKBPs consist of a family of related proteins that normally have many important cellular functions, but in Parkinson’s disease (PD) certain FKBPs play a pathological role by promoting aberrant protein aggregation. Plex’s goal is to discover small molecule FKBP inhibitors as a treatment for PD.
Hsp Response to Protein Aggregation and Misfolding
Cataract, the clouding of the eye lens is responsible for 48% of world blindness. According to World Health Organization nearly 18 million people are bilaterally blind from cataract in the world. Data dating back to the beginning of this millennium showed that 30-60% of blindness in Africa and 60-80% in South East Asia is attributable to cataracts.
The only treatment currently available is surgical extraction of the lens and replacement with an intraocular lens that is accompanied by a high public health burden with an annual Medicare costs exceeding over $3 billion. In addition, access to proper medical care required for successful surgical outcomes are limited for patients in poverty stricken countries where 90% of cataract blindness occurs. It is estimated that a delay in cataract onset by as little as 10 years could reduce the need for cataract surgery by as much as one half and result in substantial savings in healthcare dollars.
Alpha-crystallin (AC) is one of the three major eye lens crystallins and is a representative member of the small heat shock protein (sHsp) family. AC serves as molecular chaperone, protecting damaged or aged lens proteins and enzymes from aggregation that would otherwise lead to light scattering and cataract formation. It is well established that chaperone-like activity (CLA) of AC is critical for lens transparency and it is hypothesized that maintaining optimal or increasing chaperone activity might aid in the prevention or slowing of cataract. Plex is developing molecules that can interact with AC and increase its CLA to reverse, slow and/or prevent the formation of cataracts.
Plex began a drug discovery program in 2009 to seek inhibitors of HSP 90 and its mitochondrial homolog TNF Receptor Associated Protein-1 (TRAP-1). Since initiation of these studies, Plex has discovered multiple lead candidates with potential anti-cancer properties.
Preliminary studies have shown that one of our lead series has blood brain barrier penetrating properties. Our goal is to develop these dual HSP90/TRAP1 inhibitors as a treatment for CNS tumors that include glioblastoma multiforme, metastatic brain tumors, and CNS tumors associated with neurofibromatosis type 2.
Hsp Dependent Oncogenic Proteins
Plex's core technology platform effectively combines functional fragment screening with X-ray crystallography co-crystallization guided by a streamlined structure-based design approach to design and synthesize New Chemical Entities (NCEs) with drug-like properties.
For closely related target isotypes, Plex employs a differential fragment screening method as a powerful tool to identify highly isotype-selective and pan inhibitors to improve therapeutic efficacy.
Fragment-based drug discovery (FBDD) is becoming an increasingly efficient alternative to traditional high throughput screening of compound libraries in the pharmaceutical industry for the discovery of new chemical entities (NCEs). Most traditional fragment screening methods utilize physical methods such as NMR, surface plasmon resonance (SPR), and crystallography.
NMR and SPR fragment screening techniques measure molecular interactions between low affinity fragments and their target, and as such are highly susceptible to false positives arising from non-specific binding to an unrelated part of the drug target (protein or enzyme). Crystallography fragment screening yields fewer false positives, but is time-consuming and expensive.
Plex has successfully developed and optimized a cost-effective fragment screening platform based on assays that measure functional activity to greatly expedite the screening process and hit identification. Plex's function-based methodology exploits the biological function of drug targets to aid in identifying fragment hits with greater selectivity and specificity much earlier in the discovery process.
Fragment screening at Plex is performed utilizing a proprietary 1,000-member fragment library optimized for properties that have a higher probability of yielding blood brain barrier-crossing CNS “drug-like” NCEs.
Plex has also developed an advanced differential fragment screening (DFS) platform to distinguish hits against targets with related isotype forms. DFS has proved to be a particularly powerful tool for screening targets with closely related isotypes to identify highly isotype-selective inhibitors as well as pan inhibitors.
Plex's functional fragment screening platform, when combined with structural biology and X-ray crystallography, not only expedites but also yields “drug-like” leads superior in selectivity and specificity to leads identified by conventional SAR, while also offering the following added advantages:
Plex Pharmaceuticals has successfully applied this approach to identify numerous low micro to low millimolar hits for a variety of drug targets to rapidly advance its internal drug discovery portfolio.
Plex employs a wide array of biochemical assays (binding, enzyme, immunoassays) and cell-based assays (viability, apoptosis, biomarker, mitochondria uptake/function, reporter) for structure-activity-relationship studies to identify potent and selective leads. In addition to Plex’s own evolving panel of cell lines, the Plex also has access to well-characterized patient-derived cancer cell lines though collaborations with the Mayo Clinic and University of California, San Diego.
