Generian, Mitobridge (Astellas) Partner to Expand Playbook of what is Druggable
Generian CSO and co-founder, Dr. Toren Finkel/Courtesy of Generian Pharmaceuticals
The big week of partnering continued into Wednesday as Generian Pharmaceuticals and Mitobridge, a wholly-owned subsidiary of Astellas Pharma, announced a collaboration to discover and develop novel small molecules for undruggable therapeutic targets. Generian will receive an upfront payment and is eligible to receive milestone payments that could result in over $180 million for the company.
Generian, which is a subset of UPMC Enterprises, will lend its proprietary platform in the deal. The platform is a drug discovery engine designed for rapid and scalable target discovery that facilitates the identification of small molecules that can target proteins. Small molecule drugs are used to treat a variety of diseases due to their ability to pass through the cell membrane and reach intracellular targets that can be the origin of biological dysfunction.
“The technology is a way to use a high throughput screening platform that allows us to screen proteins of interest inside the cell and then a native environment or configuration to be able to detect, in a very sensitive and specific fashion, changes in confirmation in a protein of interest with and without the drug,” Toren Finkel, M.D., Ph.D., chief scientific officer and co-founder of Generian told BioSpace in an interview. “We’re able to detect the binding of novel ligands to a protein of interest in a very robust fashion that allows us to basically get hundreds of ligand binders to any given protein that we screen.”
By utilizing this technology, Generian and its collaborators are able to investigate what have been previously thought to be undruggable targets. The platform can screen and determine which compounds have the ability to bind to the target of interest and modulate protein stability.
“Conventionally, small molecules work as inhibitors, but we found that at least a subset of our binders actually affect the stability of the protein, both positively and negatively. So, we can get small molecules that increase protein stability that might be good for the cell to have more of but we can also get small molecules that bind to the protein and destabilize it, causing it to undergo proteasomal molecular degradation,” Finkel explained. “This is expanding the playbook of what drugs can do, not acting strictly as inhibitors but also altering the stability of the protein.”
Although the companies are not able to disclose the details of what diseases or conditions they might target, Generian CEO Hank Safferstein, Ph.D., said that they are looking at a variety of diverse targets that could have multiple potential disease implications that he believes are outside of the “normal cadence” of what small molecule therapeutics have targeted.
“The collaboration really leverages the power of Generian’s platform as well as some of the expertise that we’ve developed within Generian and towards the interrogation and identification of small molecule drug candidates against targets that Mitobridge is interested in,” Safferstein said. “It’s a multi-target collaboration.”
Generian’s focus as a company has been on targeting transcription factors, which play a role in transcribing DNA into messenger RNA. Transcription factors can either upregulate or downregulate genetic expression, which impacts protein expression. Targeting transcription factors could potentially result in therapeutics for diseases of protein or lipid aggregation, impaired quality control and defective pathogen clearance.
The company has also targeted AMP-activated protein kinase (AMPK) which helps to maintain cellular fitness and plays a role in cell metabolism. AMPK-targeted therapies could be useful for treating diseases of impaired energy metabolism.
“We want to expand the playbook of what’s druggable and I think there are a lot of targets that small molecules really have not been able to access. Based upon what we see using transcriptional factors, we’re very encouraged that this might be a way to go after those types of targets. Obviously, oncology, metabolism and inflammatory diseases are regulated in many ways at the transcriptional level, and that is something that excites us moving forward,” Finkel said.
While the collaboration plans to develop small molecules that target transcription factors that can act as molecular degraders, Generian is also interested in epigenetic modifiers. The platform is agnostic, and also offers benefits such as rapid scalability with the ability to quickly demonstrate proof of concept in preclinical phases.
“Our collaboration with Generian is an exciting and transformative opportunity to accelerate our drug discovery activities in the area of [the] undruggable target space,” David Barrett, Ph.D., president of Mitobridge, said in a press release. “We are very excited to work with a world-class team of collaborators to deliver significant new treatment options for patients suffering from currently intractable or poorly served diseases.”